	In today’s era of news sharing, you can’t be too careful about what you listen to, and what you believe. And since data sources are ceaselessly multiplying, the challenge becomes all the greater in deciding how to sort through the growing floods of information, misinformation, and disinformation. Amidst all of that, how are drug developers to keep their heads above water?

	This is the challenge that European health authorities are now beginning to take more seriously-as is demonstrated by a flurry of recent initiatives, and most notably by a mid-February report from the big guns of the regulators. The European Medicines Agency (EMA) and the heads of more than a dozen of Europe’s national agencies 

 on how to respond to the proliferation of threats and opportunities from big data.

	Just as a taster, the initial recommendations relating specifically to clinical trials range from the obvious to the ambitious. “Data standardization activities are critical to increase data interoperability and facilitate data sharing,” concludes the study, unremarkably. So it is necessary to agree on data formats and standards for regulatory submissions of raw patient data, via strong support to the use of global data standards, and for alignment with other regulatory bodies.

	A big upgrade to the use of individual patient-level data in regulatory processes is envisioned. Direct access should be routine during review of marketing authorization applications, and authorities should have greater capacity and skills for analyzing this material and better imaging expertise, says the report. And pilot studies should be set up to define innovative outcomes from imaging data, and to determine the validity of computer-aided evaluation of images.

	Still more radically, the authorities recommend systematic sharing of clinical trial data submitted for regulatory assessment. They want to see “a data-sharing culture” in Europe, in which there is full recognition of the value of clinical data sharing for drug development. “The vast majority of clinical trials are never submitted as part of a regulatory submission and standardization activities are critical to increase data interoperability and facilitate data sharing,” the report points out. So here too, it urges pilot studies to show the value of sharing of clinical data that has regulatory relevance-such as identification of safety signals, product class comparisons, and indirect comparisons of closely related medicinal products.

	The report is just the first output from the joint taskforce set up by European regulators, based on the conviction that “a regulatory strategy is required to determine when and how in the product lifecycle evidence derived from such data may be acceptable for regulatory decision-making.” It offers a definition of big data, and reviews the data landscape in genomics, bioanalytical ‘omics (with a focus on proteomics), clinical trials, observational data, spontaneous adverse drug reaction (ADR) data, and social media and mHealth data. It recognizes that data may reach regulatory authorities as supportive data in the margins of more traditional analyzed structured data, or may underpin a regulatory submission as a whole. “It is thus essential that the regulatory network understands its presence and the robustness by which it was generated in order to make a competent evaluation of the submission as a whole.”

	The current deficiencies in Europe’s capacities are catalogued. A survey of national competent authorities revealed “very limited expertise in big data analytics at national level”; “Eight of 24 reported no in-house expertise in biostatistics;” and “maintaining sufficient expertise within the regulatory network will be an increasing challenge.” Concerns highlighted by industry in exploiting big data sets included data access, data integration, data validation, and data reproducibility, as well as data security and data protection.

	The needs are as great beyond Europe as within Europe, the report notes. “From a regulatory perspective, global cooperation is important, as for many rare diseases and cancers or indeed rare ADRs, there may only be a handful of cases worldwide and these data need to be interoperable to derive meaningful insights.” But the particular challenges of operating across broader geographies are acknowledged, too. The report goes on to warn that “on a global level, it is important to ensure that extremely expensive and time-consuming initiatives do not pull in opposite directions but work together to achieve sustainable and global solutions.”

	Similarly, there are “multiple barriers” to data-sharing in sufficient depth and detail so as to retain its utility, not least with increasingly complex data from multiple sources. Europe has a poor record in this: “Europe has failed to define a clear path to enable sustainability of many previous data-sharing efforts, particularly for observational healthcare data, and defining this should be a priority in the future,” the report states. But in addition, meeting data protection obligations on a global scale requires urgent development of global guiding principles and standards for data anonymization, it insists.

	On top of that, there are more self-interested barriers: “Data sharing is additionally hindered by a reluctance to share data in order to promote individual career ambitions or protect potentially commercially valuable information,” and these demand some new mandatory elements to drive sharing.

	The report takes the form of a summary of its reflections so far, published in order to gather comments and responses from stakeholders (you have until April 28 to take a look at the document and make your own views known). Meanwhile, a further group looking at cross-cutting data-processing and analytics is due to deliver a subsequent report in the first half of 2019. Early indications are that this will recommend formation of a standing advisory group to explore the applicability of big data analytic methodologies, standards, and IT architecture, so as to support the development, scientific evaluation, supervision, and monitoring of medicines. Validation of novel analytical approaches and the clinical relevance of the derived endpoints will be a key part in defining their acceptability, especially for algorithms, the European group is expected to urge.

 is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium 

Articles

News

Recent initiatives demonstrate that European health authorities are serious about combatting the proliferation of threats and opportunities from big data.


Cutting Big Data Down to Size in Europe

For the past several years, there has been increasing discussion of what patient centricity means in clinical trials. The premise is that better study designs, approaches, and services that are focused on the needs and preferences of patients can improve clinical research participation and, therefore, help advance the development of medicine and medical devices. Yet, despite the focus on this concept, the general consensus is that much work remains to realize its potential.

 by the Center for Information and Study on Clinical Research Participation (CISCRP) has shown that patients typically partake in clinical research for both altruistic reasons and with hopes of benefiting their personal health. Other research has also begun to identify what patients want when participating in a trial.

	While this is valuable research, the industry hasn’t addressed some important questions: Do patient needs and preferences vary by condition and other patient demographics? Could gaining a better understanding of patients’ lives and the factors that affect their decision to participate in the trial help to create a more attractive patient experience? Is it time to think about making the studies fit the patients’ needs better? What would it mean to move away from viewing patients as subjects in medical research, and engaging them as the stakeholders they are?

	During the summer of 2018, Antidote Technologies and SCORR Marketing partnered on a survey to gain a deeper understanding of patient perceptions of clinical trials and their motivations to participate. The survey also was designed to identify differences related to condition, household income, education, ethnicity, and gender.

	Survey participants were recruited to participate by Antidote’s partners: American Kidney Fund, Allergy & Asthma Network, Healthline, JDRF, Lung Cancer Alliance, Lupus Research Alliance, Melanoma Research Alliance, and Multiple Sclerosis Association of America. Each partner organization distributed the survey to its membership through a combination of emails, website posts, and social media posts. Some worked with other partner organizations in their disease area to generate responses from caregivers and patients.

	Of the nearly 4,000 survey respondents, the majority (89%) identified as a patient. Twenty-seven percent of respondents have multiple sclerosis (MS), 15% have asthma and/or allergies, 13% have kidney disease, 12% have melanoma, 12% have type 1 diabetes, 10% have lupus, 6% have lung cancer, and 5% have gastrointestinal disease. Twenty-six percent of respondents had participated in a clinical trial at the time of data collection.

	Most survey respondents (84%) had at least some college or a college degree, and more than half (53%) reported an annual household income of less than $75,000. The sample skewed older (74% of respondents were over the age of 45), white (90% of respondents), and female (80%).

Patient motivators for participating in medical research

	Providing prospective patients with the right information to make a decision starts with understanding what drives patients to join a trial in the first place (see Table 1).

	Of the 26% of the respondents who had previously joined a clinical trial:

		75% reported that the major reason or one of the major reasons they joined the clinical trial was to help future patients.

		69% said they participated to improve their quality of life.

		63% indicated they were highly motivated to participate in order to receive the best care possible.

	All survey participants rated the importance of 16 potential motivators to take part in a trial. Each motivator was placed in one of the following categories: safety concerns, health benefits, logistical concerns, institutional support, and financial benefits. The percentage of the survey population rating the type of consideration as very important and the average ordinal ranking (where a lower number indicates a higher ranking; see Table 2).

	When we asked respondents about the possible motivators to participate in a clinical trial, unsurprisingly, safety topped the list of priorities. Seventy-three percent said it was very important that the research not interfere with their current treatment or make their conditions worse. This was the chief safety concern expressed. Of the eight condition categories included in the survey, patients with kidney disease assigned the highest importance to the idea that the clinical trial should do no harm.

	Having someone available to answer questions throughout the study (66%) and their doctor’s support for their decision to participate (50%) were important to respondents as well. Lung cancer and melanoma patients were most likely to deem it “very important” that their doctor supports their decision to join a clinical trial. Women are more likely to value the importance of having their questions answered throughout the study.

	The potential to benefit their personal health was also important to the respondents. About two-thirds (67%) of respondents identified this statement as the top health benefit: “The trial provides me with a drug, therapy, treatment, or medical device that potentially could extend or improve the quality of my life.”

	Logistics play a role in decision-making as well. Respondents felt it very important that they could complete the entire trial. More than half (59%) of the respondents deemed this as very important and the top logistical concern. Patients with kidney disease, MS, or allergy/asthma place a higher priority on logistical factors than patients with other conditions. Overall, only a minority of respondents said it is very important that a trial doesn’t take time away from their obligations and, similarly, only a minority considered it very important to have clinical researchers make home visits.

	Financial benefits, while very important to some, are generally viewed as less important than other considerations. Oncology and type 1 diabetes patients were the least inclined to be concerned with financial considerations. Less than half (46%) of the respondents said being compensated to participate would be a motivator; however, younger respondents or those with lower household incomes were much more inclined to believe compensation would be a motivator to participate. 

	A key element of patient centricity may relate to the industry’s ability to truly embrace patients as partners. And this effort revolves around medical professionals:

		90% said that talking with doctors, clinical trial coordinators, and nurses involved in the research would either “very likely” or “likely” help them feel more like a partner in the research.

		Older patients have a stronger preference for talking with not only medical professionals, but also other patients like them or the hospital or company responsible for the project.

	However, despite the influential role medical professionals have, only one-third of these respondents have ever talked about research with their doctor.

	Similarly, having the necessary information to make well-informed decisions about participation is a key theme that runs through many of the patient responses:

		77% want the industry to make it easier to learn about clinical trials.

		70% would like information about findings from clinical trials to be more readily available.

		66% desire clearer information about the costs that they will incur (time, financial, etc.).

		56% want healthcare professionals (HCPs) to speak with them about  clinical research before discussing participation in a specific trial.

	The results of the survey raise important points about clinical research:

		Patients with life-threatening conditions are most concerned about gaining access to treatments.

		Individuals whose condition limits their mobility are concerned about logistical factors.

		People with asthma or allergies-a condition that impacts low-income people more-are concerned about the financial obstacles to participating in medical research.

	More important than these findings is the confirmation that there is not a one-size-fits-all solution for engaging individuals in medical research. Rather, it is important to consider the particular obstacles facing patients when they are making decisions about whether or not to partake.

	Providing information is a start. While survey respondents showed a clear preference for receiving information about clinical trials from their doctor or other HCP, 49% want to receive information from patients who have previously participated in a clinical trial (especially true for minority patients who haven’t joined a trial before), and almost twice as many preferred to receive information from an advocacy/nonprofit organization or health and wellness website (42%) than from a drug company or advertisement.

	In addition to the survey findings, issues like low health literacy and the growing use of the internet for health information point to the need to better engage patient advocacy groups and medical professionals not only in recruiting participants for clinical trials, but also in raising awareness of clinical research as a care option and dispelling common myths that may discourage participation.  

Patient communities and advocacy groups can help bridge the knowledge gap to improve health literacy, give patients access to former clinical trial participants, provide information about clinical trial opportunities, and direct patients to the best places where they already are searching for information-online.

	To that end, we also need to be smarter about our methods of communicating. Digital solutions provide one avenue to reach patients, but we need to think about how we leverage digital tools to facilitate two-way conversations. While we understand that interpersonal communication with medical professionals is an essential part of the patient recruitment, screening, and consent process, too often we limit important conversations by failing to use all the tools available, like message boards and online communities.

	These avenues are important: Our survey revealed that about three in five respondents use message boards and health-based online communities to learn more about their condition and the experiences of other patients. And about two-thirds of melanoma, gastrointestinal disease, lung cancer, lupus, and type 1 diabetes patients use message boards and health-based online communities to learn more about their condition and the experiences of other patients. This is particularly true among younger digital natives.

	Yet, as any behavior change specialist can attest, information is not enough. As an industry, we must also remove barriers to participation by considering the burden placed on participants as the trials are designed. The industry needs to include better and more robust mechanisms for patients to participate at early stages of research planning from protocol design to endpoint selection.

	This collaborative approach has been supported by the FDA as well. Under PDUFA V, the agency is conducting disease-specific patient-focused drug development (PFDD) meetings with key stakeholders to obtain patient perspectives on specific diseases and treatments. The FDA also supports externally led PFDD meetings such as the Lupus Patient-Focused Drug Development (PFDD) meeting. These meetings and subsequent reports seek to give patients a voice in what researchers are investigating in addition to how the research is conducted.

	At the start of the survey project, we set out to answer the question: How can researchers engage patients in a way that makes them feel like stakeholders, rather than subjects, in research? What we learned is that while different patient populations have different specific desires, the underlying theme is that patients want more information from medical professionals, advocacy groups, and their peers.

	The key takeaways from our efforts include:

 Patients want to be well-informed and empowered consumers of health information.

		Industry has a role to play here, especially with regard to health literacy. Reallocating marketing spend from advertisements to educational materials or grants for health-focused nonprofit organizations may aid in developing the confidence healthcare consumers need to consider clinical trials as a care option.

 We need a more collaborative planning process that incorporates all stakeholders, especially patients.

		Patients want a say in what new treatments are researched and how they are tested, and they are willing to share their ideas and thoughts through participatory design processes. Having the right trial design for the right patient population may significantly reduce recruitment timelines and get new treatments to market faster.

		There is a benefit to leveraging patient communities and advocacy groups since they are patient-focused and understand the nuances of specific conditions. Our research found what motivates patients to participate in a clinical study varies with condition and other demographic data, and patient organizations have valuable insight into engaging these patient groups. Patient advocacy groups are also expert communicators and can convey information about clinical trials and answer questions and concerns from patients and caregivers when they are seeking that information.

Data and technology companies and collaborations are increasingly important, but a human touch is still necessary. 

		The addition of electronic health records (EHRs) to identify sites with potentially eligible patients can further add to the recruitment funnel, but without an understanding of which patients are interested in participating in medical research, these initiatives can fall flat.

		It is important to have mechanisms to quickly engage patients once they express interest in a clinical trial, and our data clearly show that the majority of patients would prefer that follow-up include interpersonal communication.

		Sites should ask patients who have already participated in a clinical trial to share their experiences with other patients considering joining a trial either by arranging phone or online conversations or by helping them create online videos. The ability to speak with or learn from other patients was an important factor with study-naïve respondents.

		Make data sharing and technology easy for patients and sites to use by standardizing processes and improving data sharing. Technology should reduce the burden of on-site staff and trial participants and make it easier for them to communicate and share information.

 Build lasting relationships with patients for improved retention, repeat study consideration, and continuous process improvement initiatives.

		Treat patients as the research stakeholders they are and establish an ongoing flow of easy-to-understand information about the study progress and results to all participants during and after the trial.

		Utilize surveys and focus groups. Data collected from patient surveys and/or focus groups can inform future protocol design and clinical endpoints selection and facilitate investigator quality management.

		Create long-term relationships with patients before, during, and after the study with ongoing engagement programs that are specific to their preferences and needs.

	As an industry, we need to do a better job of two-way communication from the start of trial design through to sharing the results. Patients are stakeholders in the research process with an equally strong interest in seeing new treatment options come to market. Yet, the barriers we present to their ability to engage with the research process in a meaningful way outside of clinical trial participation limit this collaboration and may reinforce feelings of unease and distrust. By improving our mechanisms for listening to and engaging patients at all stages of research design in a way that is meaningful to them, we can finally begin to move the needle on patient centricity and truly understand the power the concept holds.

, MPH, CPH, is Head of Partnerships, Antidote Technologies Inc.; 

 is Senior Strategic Advisor and Director of Market Intelligence, SCORR Marketing

Feature Articles

Survey uncovers deeper learnings of patient perceptions of clinical research and the motivations to participate.

The Patient Perspective on Clinical Trials

	A surge in R&D for cutting-edge cellular and gene-based medical treatments is prompting FDA officials to spell 

out more specifically its plans for streamlining and modernizing plans for assessing and regulating these products. Main initiatives involve expanding the agency’s cadre of experts tasked with evaluating innovative cell and gene therapies and clarifying clinical research policies and strategies for this area.

	FDA anticipates that sponsors and researchers will file more than 200 investigational new drug applications (INDs) for these products by 2020, adding to the more than 800 applications currently on file for cell-based or directly administered gene therapy applications. That pipeline will lead to the approval of 10 to 20 new drugs in this area by 2025.

	Academics and research organizations are similarly enthusiastic. The MIT Focus Project, which seeks to devise new coverage and payment methods for innovative, but costly, cell and gene therapies, predicts the approval by 2030 of 40-60 important curative products in this field; these will treat about 50,000 patients and cost more than $200 billion a year.

	These advances reflect a “turning point” in the development of these technologies and their application to human health, observed FDA Commissioner Scott Gottlieb and Peter Marks, director of the Center for Biologics Evaluation and Research (CBER), in a 

. They provide an update for the biomedical research community on agency initiatives in this area, noting similarities to the accelerated growth of antibody drugs in the late 1990s. Recent advances, they observe, have been spurred by the development of safe and effective vectors for delivering gene therapies to patients.

	To continue these gains, FDA plans to add 50 reviewers to expand the expert staff in CBER and other relevant offices. The aim is to bolster the group charged with overseeing the clinical investigation, development, and review of these products. A main challenge is to recruit high-level scientists and medical officers, a continual difficulty for the agency.

	Meanwhile, more FDA guidance documents aim to clarify policies and further advance innovation in this area. A recent advisory outlines how sponsors may use expedited programs to advance regenerative medicines, including the regenerative medicine advanced therapy (RMAT) designation and accelerated approval options, to facilitate the development of cellular and gene therapy products that offer meaningful improvements over available treatments for serious or life-threatening conditions. And to encourage the development of treatments in certain promising medical areas, the agency will publish guidance on developing gene therapies that target neurodegenerative disorders. Further advice will address inherited blood conditions such as hemophilia, where oversight and study requirements may vary depending on the effect of a gene therapy on a disease target. With accelerated approval approaches, FDA also will require post market follow-up studies to assess risks and possible side effects that cannot be determined prior to approval.

	At the same time, the agency will seek to assist small firms and academic investigators that may be skirting FDA regulation for fear of being required to run costly clinical studies and to meet complex research requirements. Here, FDA plans to outline innovative trial designs that permit researchers to pool clinical data for products utilizing a common manufacturing protocol and product quality specifications.

	This initiative reflects the agency’s interest in encouraging industry to adopt more modern and reliable ways to manufacture these innovative products by reassuring sponsors that additional clinical trials may not be necessary to support all changes in production processes. Guidance here will explain that in certain situations, limited bridging studies and additional real-world data may be sufficient following production changes that implement advanced technologies. At the same time, bridging studies may be needed when more than minor changes are made in manufacturing processes, a topic that will be discussed by agency and research experts at a public meeting.

	While emphasizing flexibility in dealing with these innovative therapies, FDA also intends to expand enforcement actions to rein in operators that promote unregulated treatments without complying with regulatory policies. The agency is stepping up challenges to organizations and clinicians administering gene therapies without FDA oversight and approval, which thus raises the potential for compromising safety.

 is the Washington Correspondent for Applied Clinical Trials 

FDA officials provide more specific plans for streamlining and modernizing plans for assessing and regulating products for cutting-edge cellular and gene-based medical treatments.


FDA Clarifies Research Policies on Cell and Gene Therapies

Issue PDF

Click the title above to open the Applied Clinical Trials March 2019 issue in an interactive PDF format.

Applied Clinical Trials, March 2019 Issue (PDF)

Over the last decade, we have seen a massive “uberizing” transformation of consumer economy, in which

 individuals now have control of many of their personal properties to be made available to others at a price. As the shared economy continues to expand, we are seeing companies launching similar models around personal data.

	This development could help address some of the biggest challenges in healthcare-delivering treatment and care for those with unmet needs, especially those people affected by rare diseases.

	LunaDNA and Hu-manity.co are examples of companies looking to enable individuals to own and transact their medical data. Luna DNA received SEC approval of monetary values of an individual’s own genomic and related health data. While promising, it will take time to gauge major results, which begs the question-what’s being done now to develop therapies?

	With treatments available only to around 5% of the 7,000 rare diseases, or about 10% of the 30 million affected individuals in the US, the challenge to take on rare disease is beyond just the numbers. Historically, the biopharmaceutical industry has gravitated away from rare disease drug development due to the perception of high risk and, ultimately, the profitability question. Nonetheless, organizations like the Cystic Fibrosis Foundation, which supported development of Kalydeco by Vertex, and other trailblazers in the non-profit patient advocacy space have begun to build a paradigm required to speed rare disease research by mitigating risks and obstacles for the industry, patients, regulators, and other key stakeholders in the research ecosystem.

	The Children’s Tumor Foundation (CTF) has recently built a new integrated R&D accelerator model to provide critical resources and infrastructure, that has been lacking to researchers, to properly study and translate their studies into clinical programs. In this particular case, CTF focused on applying the model toward neurofibromatosis (NF). It established an NF patient registry to enable nature history studies and patient recruitment, an NF biobank to support researchers accessing well-characterized tissues and samples, a preclinical consortium, and an NF data hub. CTF also fostered a network of NF key opinion leaders, NF academic researchers, and NF clinicians for standardizing diagnosis and outcome measures.

	Of all these elements, recruiting patients to participate is critical, and the 10,000-member NF registry has supported recruitment needs for 20-plus clinical trials. The establishment and availability of such infrastructure can affect the go/no-go decision for industry to invest in rare disease drug development.

	We are seeing many other patient advocacy organizations swaying away from a traditional model of granting academic researchers to now supporting biotechnology and pharma companies. In addition to the financial grants received by Tocagen from the American Brain Tumor Association, National Brain Tumor Society, and Accelerate Brain Cancer Cure, the help from the patient advocacy organizations with clinical trial recruitment significantly reduced the recruitment barrier that many other companies almost always face, especially with rare diseases.

	Another noteworthy patient advocacy organization is the Hereditary Neuropathy Foundation (HNF). HNF has been focusing on accelerating R&D for those affected by the rare disorder Charcot-Marie-Tooth (CMT) and other inherited neuropathies. Unlike other monogenic-based rare diseases, CMT is comprised of multiple genetic diseases, which makes it much more difficult and complex for researchers to study.

	This amount of collaboration among industry, academia, government, non-profit foundations, and patient advocacy organizations has resulted from the unique sets of inherent challenges in rare disease drug discovery and development. And as other companies complement these efforts by continuing to build application programming interfaces (APIs) to enable individuals to share data easily within the research ecosystem, every rare disease patient will have the opportunity to help propel drug discovery.

A Closing Thought

Patient advocacy organizations are swaying away from a traditional model of granting academic researchers to now supporting biotechnology and pharma companies.

The Rise of Shared Digital Health Economy and Promise of Accelerated Clinical Research

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 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

A case study of a Parkinson’s disease trial demonstrates how one study team met its enrollment goals.

Developing an Effective Multimodal Recruitment Plan

Putting patients at the center of clinical research is a continued challenge. Barriers to getting people more involved are numerous: lack of awareness, lack of health literacy and education, mistrust or desire, physician awareness or aptitude, lack of a cohesive healthcare to research pathway, lack of patient involvement in trial design, ability to find a trial, ability to adhere and stay motivated in a trial…all of these factors and more go into the overall challenge of patient centric initiatives. On the pharma R&D side, too often the focus on patients is a transactional one, solely to improve patient recruitment, which has proved ineffective and misguided. However, many positive initiatives exist in patient centricity, and this issue, along with the March issue of 

 regularly reports about patient centricity initiatives. In 

, he summarizes the advances since he began corresponding in 2014. He notes that the FDA suggested that industry wasn’t involving the patient during the entire drug development process, and that “the industry should focus on why they are bringing drugs to market, incorporating patient diversity, and generating outcomes meaningful to patients. FDA suspected the disconnect in patient centricity interpretations arose from C-suite level personnel within the biopharmaceutical industry.”

	The need to involve patient advocacy groups as a way of gaining patient insight is a growing movement and one that is shifting from a transactional, less-involved relationship to one that is more strategic. However, that too faces a holistic patient view as a challenge when within sponsor companies themselves, the patient advocacy or patient-centric function can be divided between research and commercial. As Joel Beetsch, PhD, vice president of patient advocacy at Celgene, notes in a March article in 

, “[Manufacturers] can have two different types of patient advocacy organizations. One might be in a center of excellence within their R&D community that is really working to recruit clinical trials. Then there’s a separate function that is more associated with the business. Often, those two functions within the same company don’t communicate regularly with one another.” And while this can be common practice, Beetsch says that is not the case at Celgene, where all of those activities are in one department.

	Finally, patient education and awareness is another key piece missing in clinical research. In this issue, The Center for Information and Study on Clinical Research Participation (CISCRP) 

 of the evolution of its own services to the patient community as a non-profit organization. At the end of the article, the authors note, “The objectives of awareness and clinical research literacy are no longer to primarily increase patient recruitment rates. They have evolved to accommodate patient needs to influence and be a part of each patient’s healthcare and treatment decisions; build confidence and a personal sense of control in one’s own health journey; enable key stakeholders to facilitate participations; to elevate appreciation for all study volunteers; and to demonstrate the personal relevance of clinical research participation.”

From the Editor

Patient advocacy groups, patient centricity initiatives, and patient education are the key to putting patients at the center of clinical research.

The Road to True Patient Centricity

Mass media coverage and popular cultural depictions of clinical research during the past decade have continued to grow. For the vast majority of the public, these channels are the dominant educational medium, becoming even more so with the rapid influx of programming and content that can be easily accessed and streamed over the internet and shared on social media. Most of this exposure-unfortunately-has been negative and/or unbalanced, focusing largely on risks, human error, and questionable motives.

	During that same timeframe, new and expanded programs and initiatives designed to raise public awareness and improve clinical research literacy-particularly among minority and underserved communities-have been implemented. This article looks at the current environment for public and patient awareness and education and discusses changes that the Center for Information and Study on Clinical Research (CISCRP) and others are making to be more effective. These approaches have refined the focus of educational content and have better leveraged the reach and frequency of these outreach and communication channels. CISCRP’s novel programs are having an impact, and they are evolving and expanding to counteract the effects of wide-spread negative and unbalanced exposure.

	Broad reach, high frequency, and the integration of communication formats have reinforced and expanded the impact of news, entertainment, and social networks, but coverage is typically superficial, uninformed, and sensationalized. News media, for example, has no shortage of clinical research-related topics to write about, but news bureaus operate with leaner editorial staff today and rely increasingly on freelancers. And most journalists have little to no prior knowledge about clinical research and must hastily gather information and interview quotes while facing tight deadlines and editorial demands for headline-grabbing coverage. As a result, although some articles profile patients and families that have found hope in clinical trials and investigational treatments, the majority provide a negative and often sensationalistic focus on mistakes made by clinical research professionals, concealment, fraud, and corruption. 

	Given their expansive scope, the full reach of these channels is difficult to gauge. To assess frequency and positioning, CISCRP reviewed a convenience sample of content that appeared in newspapers and in film to assess how clinical research is depicted over time. We compiled and evaluated articles focusing specifically on patient experiences in clinical trials that appeared in three major national newspapers-

-between 2016 and 2018. The results of this assessment were compared with a similar approach conducted 15 years ago at CISCRP’s inception. We did not count the educational supplements that CISCRP has been recently producing and distributing through 

	We observed a 27% increase in the number of articles that appeared in these major newspapers-33 that appeared in the 2001–2003 timeframe and 42 in the 2016–2018 period. We found that the proportion of articles that offered unbalanced, negative coverage had not changed during the 15-year time horizon. In the earlier period, 59% of the articles were negative; 60% of the articles were negative in the more recent period.

	Trends in fictional film and television-two popular culture mediums with extensive reach-are even more alarming. There were very few films and TV movies focusing specifically on patients in clinical research in the 2003 timeframe. 

, starring Ralph Fiennes and Rachel Weiss, was released in 2005, and it focused on a healthcare activist murdered before she was able to expose a large pharmaceutical company that had been exploiting a vulnerable population of study volunteers. In 2018, we identified 10 major fictional stories in film and TV including 

 with Rooney Mara, Channing Tatum, and Jude Law; 

 with Emma Stone and Jonah Hill. Each of these films depicts experimental treatments and procedures for severe and chronic medical conditions that have run amok. In 2017, Oprah Winfrey starred in a movie for HBO based on the best-selling book 

. The film told the true story of HeLa cells, one of the most commonly used cell lines in scientific research, gathered without consent or remuneration to the patient and her family.

	Although it is not their primary objective, the star power and story lines in these movies arguably reach and influence the largest audiences. All but one of these fictional movies provided any information that might help educate and inform patients with diverse medical conditions about clinical research and the participation process.

	There is a silver lining. Most coverage in the mass media and in popular culture-including film and literature-is removed from and lacks personal relevance to a large percentage of its audience. The themes and messages are not tailored or targeted. They are unable to address the highly personalized nature of each person’s health, medical journey, and learning style enhanced by interactions with trusted advisors in individualized locations and communities. 

	Coverage in the news and in entertainment media is not coordinated and integrated into the many systems and stakeholders that facilitate patient engagement. Numerous studies in the literature demonstrate that clinical research participation is a team-based undertaking: patients rely on their personal healthcare providers and trusted family, friends, and professionals to make decisions and follow-through with their participation in clinical research.

	CISCRP’s awareness-building and education strategy has been evolving to take advantage of these weaknesses.

Expanded and new public and patient awareness and education models

	AWARE for All was CISCRP’s first public and patient awareness and education campaign, launched in 2003. At that time, we announced the new program in 

. It is a live event, produced in major metropolitan areas in the U.S. and to a lesser extent in Europe, that requires six to eight months of planning and awareness-building to engage patients, the public, local health and clinical research professionals, minority community centers, lay leaders, and community-based disease and patient advocacy groups. AWARE’s success depends greatly on the active participation and support of local stakeholders and the accessibility of the event to public transportation. 

	Since its introduction, AWARE’s format and outreach strategy have adapted to better accommodate local needs and attract diverse communities. From the outset, CISCRP has developed educational material with input from patients and the lay community to ensure that it is culturally sensitive at the grassroots level. Between 2003–2012, CISCRP hosted three events annually, typically on a Saturday as a full-day program with nine or 10 breakout workshops.  Three to five free health screenings were provided at these AWARE programs. Depending on local community involvement location, each program received between 150 and 250 attendees. While audience members enjoyed extensive educational programming with an opportunity to select workshops of interest, many attendees suggested CISCRP consider a shorter program format on a weekday evening to accommodate busy weekend schedules and family time.

	Since 2013, the AWARE program format has been modified to improve convenience, address time constraints, and to increase value and relevance. The programs are held on weekdays-Tuesday, Wednesday, or Thursday-typically between 5–8 pm. We have tripled the number of free health screenings. And CISCRP has increased the number of programs to include four to six cities each year. 

From the outset, CISCRP has marketed and promoted AWARE through paid advertisements in local newspapers, social media, printed flyers and postcards, mailed brochures, public transit advertisements, press releases, media alerts, radio and TV public service announcements (PSAs), and community calendars. We have also developed a promotion toolkit for local community groups to use within their own outreach channels in support of their AWARE program. Much of this marketing and promotion begins months earlier to create awareness momentum building up to the actual AWARE event.

	CISCRP places a disproportionately high investment of time and staff on local community-based approaches to facilitate awareness. We work with local advocacy groups or hospitals; encourage colleagues, family, friends, doctors, and research teams to extend personal invitations; and hold in-person conversations at health fairs and local events.

	Over the past five years, with national sponsorship from EMD Serono and the Lupus Research Alliance, CISCRP has boosted AWARE's online presence through digital event pages and sponsored social media posts. The number of impressions now reaches two million to four million in each AWARE city entered. Every program has seen a dramatic increase in average attendance, now attracting between 300 and 600 people with a high percentage from minority and underserved communities. After every event, the number of inquiries and searches for clinical trials on the CISCRP website increases by 30% to 40%. And as the program model has evolved, we have also seen an increase in the number of health and clinical research professionals and exhibitors at each event. 

In the aggregate, since 2013, 70% of AWARE attendees have been from minority communities; 71% have never participated in a clinical trial; 20% have never heard about clinical research prior to attending or receiving information about the event; and 56% report knowing very little about clinical research in general. Post-program, 83% of AWARE participants report that they are more likely to volunteer for a clinical study (vs. 43% pre-program); 94% report an interest in participating if invited by their doctor; 96% of our attendees are likely to tell their family and friends about something they learned at our program; and 88% would consider suggesting that their family or friends participate in a trial. 

	Since 2016, CISCRP has been pairing its live AWARE event with novel highly interactive and personally relevant educational programs that attract more local media coverage and create buzz and excitement leading up to the local AWARE event. After hosting each of these initiatives in underserved communities in the weeks prior to the event, CISCRP has seen event pre-registrations increase by more than 50%.

	In late 2016, CISCRP collaborated with Sanofi and creative ad agency Langland to produce an 

 in the heart of downtown Newark. A month prior to the AWARE for All - Newark program, we established a pharmacy with empty store shelves to demonstrate what modern medicine would look like without clinical trials and study volunteers. Pharmacy staff were recruited locally and trained to answer questions about clinical research from visitors to the store. Local coverage and buzz boosted registrations and long after the event, the MT Pharmacy’s important educational message continues to resonate on YouTube and other digital and social media channels. 

	CISCRP collaborated with Janssen and Wondros (another creative agency) to produce a mobile unit that traveled around the sprawling Los Angeles community in the weeks leading up to the 

. The customized recreational vehicle contained interactive displays with educational information about clinical research and about the upcoming AWARE program. CISCRP also trained local “ambassadors,” including local celebrities who volunteered their time to speak directly with the community, promote the event, answer questions, and refer the public to other resources. The Journey to Better Health initiative is now gaining visibility on social media channels and has recently received a SCOPE Participant Engagement award for its impact.

Creating ground cover with public service messages

	During the past 15 years, CISCRP and other organizations-including the Pharmaceutical Research and Manufacturers of America (PhRMA) and TransCelerate BioPharma-have increased the frequency of public and patient awareness-building campaigns and expanded reach through digital and online channels supported by dedicated web portals containing educational resources. These initiatives have also refined their positioning to emphasize the gift of study volunteer participation, the personal relevance of clinical research, and the collective contribution of clinical research professionals.

	In the early 2000s, most public service announcements focused on a specific breakthrough therapy and individual company contribution to science and innovation. Launched in 2017, 

, initiated by PhRMA on behalf of America’s biopharmaceutical companies, presents stories highlighting the bold risks that pharmaceutical and biotechnology organizations have taken to develop new treatments that improve medical conditions and public health. TransCelerate’s 2018 One Person Closer campaign (@OnePersonCloser) features stories of clinical researchers, healthcare professionals, and patients to personalize the clinical research experience and demonstrate the partnership that must exist between them. The One Person Closer campaign has been featured and discussed in past 

	Since its founding, CISCRP has developed several PSAs. All of CISCRP’s campaigns gathered input from patients, advocacy groups, and professionals and are designed to engender appreciation for study volunteers and the importance that participation brings to developing treatments that benefit society. All PSAs are still in use, with earlier messages primarily appearing on posters and websites in hospitals and in medical and research center offices.

	CISCRP’s first PSA launched in 2004-”Behind Every Medicine are the Volunteers Who Take Part in Clinical Research Studies”-was developed in collaboration with the U.S. Department of Health and Human Services (HHS). In 2007, CISCRP launched the PSA “Medical Heroes Can Be Found in Everyday Places.” When it was introduced, Eli Lilly ran the campaign concurrently with traditional patient recruitment efforts. In separate pilots, Lilly observed a 38% increase in monthly enrollment rates when a radio Medical Heroes PSA was run concurrently and a 140% increase in monthly enrollment rates when radio and TV Medical Heroes PSAs were used. Both CISCRP programs have been written about extensively in 

	Our most recent PSA, the “Medical Hero to Millions” campaign, was launched in 2018 and has expanded frequency, continuity, and reach through ongoing repeat usage in social and digital media and content licensing arrangements. In partnership with 

, CISCRP now produces a supplement every six months with individual patient stories, educational content, messages of appreciation from pharmaceutical companies (e.g., Merck & Co., Pfizer, Biogen, TransCelerate, and Lilly) and the CISCRP PSA. Each supplement reaches more than 750,000 in its printed circulation and more than one million readers through each digital edition. The PSA has also appeared in a number of print and digital publications, including the National Basketball Association's 

magazine, which reaches approximately two million people, and in Major League Baseball’s 

 magazine, reaching an estimated 2.2 million in print and digital formats. CISCRP continues to establish opportunities to extend the reach of its Medical Hero to Millions campaign.

	We are learning a great deal about how to improve the effectiveness and reach of our awareness- and clinical research literacy-building initiatives. Progress and success are due to many factors, including engaging patients and the local community around highly personal and relevant positioning; establishing customized programs in the heart of individual communities; connecting national and local outreach; leveraging a wide range of communication channels with print, digital and social media formats; coordinating and integrating educational programs and resources; maintaining frequency and continuity of messages; and enabling the integral patient-professional relationships. 

	This year, CISCRP and Janssen Pharmaceutical Companies of Johnson & Johnson are expanding the Journey to Better Health mobile educational program to include three additional U.S. cities.  CISCRP is in discussions to take the MT Pharmacy to additional inner cities in the U.S. and in Europe. CISCRP is also exploring the introduction of Clinical Research Navigators to operate within and between community centers, physician and healthcare provider communities, patients, and their families. And we are increasing the frequency and reach of our national newspaper supplements and adding a new supplement in a major European paper.

	CISCRP continues to seek funding to implement its science museum initiative designed to raise awareness and overall clinical research literacy among elementary through high school-aged children. We 

 several years ago. No science museum has ever featured and recognized clinical research volunteers. CISCRP plans to develop and exhibit to occupy a 1,000 square foot area with 10 stations offering interactivity, problem-solving, and experiential learning. The museum exhibit will travel to different cities and will generate local and national media attention and support from the local clinical research community. Children and their families will move from station to station through the exhibit, where they can hear and observe real study volunteer stories and experiences and learn about the clinical research process, one’s rights as a volunteer, and the many people who have participated in clinical trials that resulted in well-known and age-relevant new treatments. Museum visitors will have a chance to send “thank you” notes and words of appreciation electronically to study volunteers that will be posted on websites and local bulletin boards.

	We have seen a profound evolution in our thinking about building awareness. Historically, the clinical research 

enterprise focused on raising the visibility of individual companies and their breakthrough innovations. The enterprise now collectively embraces the shared need to raise awareness in a personalized way while simultaneously coordinating and integrating with the many stakeholders that support patient engagement. 

	The objectives of awareness and clinical research literacy are no longer to primarily increase patient recruitment rates. They have evolved to accommodate patient needs to influence and be a part of each patient’s healthcare and treatment decisions; build confidence and a personal sense of control in one’s own health journey; enable key stakeholders to facilitate participations; to elevate appreciation for all study volunteers; and to demonstrate the personal relevance of clinical research participation.

is Founder and Board Chair, CISCRP, and an Associate Professor at Tufts Center for the Study of Drug Development (CSDD); 

is Senior Manager, Development and Community Engagement, CISCRP

Tracking the evolution and effectiveness of CISCRP’s clinical research awareness and literacy campaigns.  

New Models to Raise Public and Patient Awareness

Real-world evidence (RWE) is a subject of increasing discussion-not to mention implementation-in clinical research, serving to supplement traditional clinical trials and offering the potential for better treatments with a faster route to market.

	Perhaps less discussed is the potential for RWE to aid another emerging priority in research design: that of patient centricity, which is rapidly becoming a priority for research sponsors as well as a common call from patient advocates.

	In this Q&A, the following participants offer their perspectives on the priorities, opportunities, and challenges of patient centricity in RWE collection: Helen Matthews, deputy CEO, The Cure Parkinson’s Trust-a leading UK charity to fund research to slow, stop, and reverse Parkinson’s; Jessica Morris, founder and chair, OurBrainBank, who is living with glioblastoma multiforme (GBM) (OurBrainBank is a US non-profit created by, with, and for patients with GBM to manage their disease and work to turn GBM from terminal to treatable); and Bruce Hellman, CEO and cofounder of uMotif, which offers a patient-friendly data capture platform for real-world and late-phase research.*

Q: What are the reasons for involving patients in research design?

 Some preclinical researchers working on Parkinson’s-related research have never met a someone living with Parkinson’s. Involving patients means those living with the condition support study design alongside the research team, either as a sanity check or more deeply as a valued and critical friend. That’s becoming normal practice in the UK, partly because funders insist on it.

	Too often patient involvement is something thought of toward the end of a process, not at its beginning. One result of not including patients early in Parkinson’s research has been a focus on movement-related issues. But non-movement issues can have a greater impact on people’s day-to-day lives: their sleep, fatigue, pain, and more. Involving patients means research is more likely to focus on things that matter most to people, delivered in a way that is relevant.

 It is hard for highly aggressive, complex, and heterogenous diseases like mine to attract research funding. Yet we can agree that the answer to the disease is likely to lie in understanding it better. Our medical research model values the objective measures of how a disease progresses, and how treatments impact-such as MRIs-over the subjective reporting from a patient, including symptoms and side effects. Patient symptom data is a largely untapped pool of information that can inform researchers, so they can better design treatments. Involving patients in that process has the added benefit of providing people with the disease to feel they are managing the disease, and not the other way round.

In this Q&A, Helen Matthews, Jessica Morris, and Bruce Hellman offer their perspectives on the priorities, opportunities, and challenges of patient centricity in real-world evidence collection.

Applied Clinical Trials-03-01-2019

Cutting Big Data Down to Size in Europe

The Patient Perspective on Clinical Trials

FDA Clarifies Research Policies on Cell and Gene Therapies

Applied Clinical Trials, March 2019 Issue (PDF)

The Rise of Shared Digital Health Economy and Promise of Accelerated Clinical Research

Developing an Effective Multimodal Recruitment Plan

The Road to True Patient Centricity

New Models to Raise Public and Patient Awareness

Me, We, And RWE: The Importance of Designing for the Patient First

Portfolio Approach to Optimize Site Selection

The Evolution of Patient Centricity

Getting Serious About Plain Language Transparency