Kenneth Getz is a senior research fellow at the Tufts Center for the Study of Drug Development.

Kenneth Getz

Of the more than 1,600 active clinical trials of treatments and vaccines for SARS-CoV-2 (COVID-19), four vaccine trials are in late stage (Phase III) activity. These promising candidates have received funding through the Operation Warp Speed (OWS) program from the US federal government. The primary aim of OWS is to rapidly develop and distribute a sufficient amount of safe and effective vaccine doses to immunize the U.S. population against COVID-19.

A look at the placement and conduct of these late-stage clinical trials offers insight into site engagement practices necessitated by global public health urgency. What do these site engagement practices tell us about sponsor confidence in meeting extremely aggressive enrollment timelines and demanding trial execution requirements? Do these practices signal a shift in where sponsors can be expected to conduct clinical trials in the future?

This article summarizes the results of a study that we have performed to answer these questions. Our goal is to assess COVID-19 site placement practices and to compare them with historical practices.

Classifying Phase III COVID-19 vaccine trials site segments

For this assessment, we have included all locations where Phase III COVID-19 vaccine studies, under Operation Warp Speed, are actively enrolling patients as of October 8th. Sponsors who were engaged in studies fitting these criteria are Moderna, Inc., Janssen Pharmaceuticals (in partnership with the Biomedical Advanced Research and Development Authority or BARDA), Pfizer, Inc. (with BioNTech), and AstraZeneca (with Oxford University).

 to identify the investigative sites participating in each of these four active Phase III COVID-19 vaccine trials. Although investigative sites in these trials continue to change, this study examines all sites that were actively enrolling as of October 8th. Data from ClinicalTrials.gov was supplemented by press releases, news articles, and other publicly available information to segment investigative sites into five categories based on the following definitions:

Site Networks (SN): defined as a collective of independent sites that derive the majority of their income from clinical research grants.This includes dedicated independent sites that are permanently part of, or affiliated with, a network. Sites within this category are generally for-profit organizations;

Academic Medical Center (AMC): defined as any site which has a major affiliation with a teaching institution. This includes any site that is a member of the Association of American Medical Colleges as a Medical School Member or a Hospital/Health System Member. Sites within this category are generally not-for-profit organizations;

Health System: defined as any entity that is, or is affiliated with, a system that includes a hospital. Sites within this category are both for-profit and not-for-profit entities. Some for-profit health systems have established not-for-profit entities within themselves for the purpose of carrying out clinical research, a factor that makes this segment difficult to classify;

Independent Medical Practice (IMP): defined as any community-based, independent clinical care provider that is not part of a larger health system. Sites within this category are generally for-profit organizations;

Government Entity (GE): defined as any site that is funded and administered by the federal government. The two major types of government entities include Veterans Affairs organizations and Indian Health Service affiliates. Sites within this category are not-for-profit organizations.

Sites supporting AstraZeneca and Oxford University’s COVID-19 clinical trial were not named in ClinicalTrials.gov; in the US, only the zip code and city name were provided.To identify and classify these sites, we used not only press releases and local news articles, but also cross-referenced the AZ site locations with sites participating in the other three sponsors’ studies.

Overall, we found that approximately half (53%) of Operation Warp Speed (OWS) clinical trials are placed within site networks; one-third (34%) of clinical trials are placed within academic medical centers; 5% within health systems; and the remaining 8% are roughly evenly placed within government entities and independent medical practices (see Table 1 below).

With the exception of Janssen’s late stage COVID clinical trials, site networks and academic medical centers operating in the US were the dominant two settings. SNs and AMCs combined to account for almost 90% of all clinical trial settings for AZ, Pfizer and Moderna programs; these two segments together account for 75% of sites conducting the Janssen clinical trial. For-profit site networks were the largest category in every clinical trial except for those sponsored by AstraZeneca, where AMCs comprised the majority.

Site networks made up at least two-thirds of both Moderna and Pfizer’s study sites; whereas they only accounted for about 40% of sites in Janssen and AstraZeneca’s clinical trials. The similar site placement patterns observed in Moderna and Pfizer’s clinical trials may in part be due to their use of the same contract research organization (PPD).

Academic Medical Centers account for over half of AstraZeneca’s sites (52%), making them the only sponsors to have engaged more AMCs than SNs.

Janssen has almost five times as many government entities as the next closest sponsor with 10% of all clinical trials being placed within federally-funded institutions. This is in part due to Janssen and BARDA’s higher relative utilization of Veterans Affairs offices.

Table 2 below shows that Janssen’s COVID-19 clinical trial is the most evenly dispersed across for-profit and not-for-profit organizations. Moderna and Pfizer are the most heavily weighted toward for-profit investigative site settings (68-70%) vs. not-for-profit settings (24%-28%).

Comparing COVID-19 trial placement to past placement practice

The most striking observation in this study is the remarkable consistency of placement practices over time including those testing new treatments and vaccines for COVID-19. In 2013, a study from the Tufts Center for the Study of Drug Development (CSDD) noted that “53% of all global FDA-regulated clinical trials are now conducted by independent, community-based principal investigators”.

 This 53% share of the total site landscape is identical to the share captured by site networks in COVID-19 vaccine trials.

Academic medical centers have held on to a more modest share of industry-funded clinical trials. In a 2007 report, Tufts CSDD noted that “today, only one-third of all industry-funded clinical trials are placed within academic clinical trials offices”.

Our study found a similar percentage —34% — of late stage COVID-19 vaccine clinical trials are being conducted within academic settings.

Academic medical centers have not been alone in their inability to increase market share of industry-funded clinical trials. Government entities — such as Veterans Affairs offices — have captured an even smaller share of this market. This is due in part to the protracted contracting, negotiations, and bureaucracy that historically contribute to slower study start-up times there when compared to that of site networks and dedicated investigative sites.

 Academic medical centers have leveraged their experience, prestige, infrastructure, and patient volume to maintain their market share. The VA setting, on the other hand, has been a consistently less attractive place for industry-funded trials.

 During the pandemic, with increased interest in public-private collaboration, the VA setting for industry-funded clinical trials will likely receive greater visibility.

Comparing sponsors of late stage COVID trials, those companies most closely collaborating with government and non-profit partners (e.g., AstraZeneca and Janssen) have placed their clinical trials in a higher relative percentage of academic medical centers. In the case of AstraZeneca, this decision is consistent with the company’s historical site placement practice: In 2007 AstraZeneca’s R&D director Ellis Wilson remarked that, “by mitigating bottlenecks on the critical path, academic sites are becoming more attractive and may even start to account for a growing proportion of trial placements. The pendulum is swinging back in their direction. And pharmaceutical companies want to be their partner of choice".

In the past, sponsors have relied on independent, for-profit investigative sites when speed and efficiency are paramount. In today’s COVID-19 vaccine landscape, the same holds true. Moderna and Pfizer’s studies, with their heavy reliance on for-profit sites, are moving the fastest in the race to prove the safety and efficacy of their vaccines.

Given the consistency observed in investigative site placement practices, we can assume that there will be a similar consistency in sponsor experience with participant diversity and inclusion for their COVID-19 trials. We can expect to see the same levels of proportional representation by participant demographic subgroup: White and Asian participants will be overrepresented, and participants from minority communities — most notably those of Black and African descent — will be underrepresented. This is particularly concerning given the higher observed rate and severity of COVID-19 cases among minority communities. Indeed, a lack of diversity has already been documented in both the NIAID Adaptive Covid-19 Treatment Trial (ACTT-1) and the Gilead-funded remdesivir study.

It is interesting to note the very low percentage of investigative sites from health systems and independent medical centers participating in these late stage COVID-19 clinical trials. Although these segments offer access to a large volume of patients within clinical care settings, combined they account for less than 10% of total sites. Similar to pre-pandemic conditions, these entities have been less attractive settings when compared to site networks and academic medical centers that offer larger numbers and more dedicated personnel; higher levels of experience and competency; and substantially greater research infrastructure.

 Hospitals and independent medical centers were also the slowest to respond during the early stages of lockdowns throughout the US, and these sites were among the most likely to suspend their clinical trials at the outset of the pandemic.

Community hospitals often find themselves being passed over during site selection in favor of academic medical centers which boast experienced investigators and specialized researchers.

 This is another reason why new investigators and health systems are not participating in COVID-19 clinical trials: sponsors place a high value on prior experience rather than total potential for accessing and attracting a large and diverse patient population. This fact makes it difficult for new investigators and sites to get their foot in the door for new clinical trials, and nowhere is this trend reflected more than in this research. Sponsors and CROs are choosing to place their study sites within entities that have proven track records, and the result is that site networks and AMCs account for over 85% of late stage COVID-19 vaccine trial sites.

Some independent medical practices and health systems are turning to partnership as a way to win and participate in more trials. The integrated research organization (IRO) is an emerging model that is allowing multi-specialty practices and community health systems to be involved in clinical trials as a research care option for their patients. Privia Health, Tryon Medical Partners in Charlotte, North Carolina, and the AMC of Wake Forest University Health, for example, are benefitting through partnership with IRO Javara Research to participate in COVID-19 vaccine trials which other health systems in the same geographic areas in some cases have not managed to secure. We can expect to see these integrated research partnerships become more common as other health systems and medical practices recognize the high-profile COVID-19 studies that IRO partners have been able to win.

In the race against time, during a pandemic that has, to date, claimed nearly 250,000 lives, sponsors and CROs are placing their COVID-19 clinical trials in the same places that they have been doing so for decades. Site networks and academic medical centers continue to dominate- and the majority are based in the US. Independent medical practices, health systems, and government entities are playing a relatively small role in late stage COVID-19 clinical trials. Sponsor company site placement practices may likely contribute to participant disparities by race and ethnicity typically seen in pre-pandemic clinical trials unless remedial and innovative approaches are utilized.

https://www.appliedclinicaltrialsonline.com/view/principal-investigators-take-lead-fda-regulated-studies

Getz KA. Industry Trials Poised to Win Back Academia. Applied Clinical Trials. 2007; 0(0) para. 3, 22. Retrieved October 8, 2020, from 

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Getz KA, Lamberti MJ, Chakravarthy R. Assessing Practices & Inefficiencies with Site Selection, Study Start-Up, and Site Activation. Applied Clinical Trials. 2016; para. 4. Retrieved October 8, 2020, from 

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Salzman S. The VA Gets Real on Reform. Applied Clinical Trials. 2019; 28(9): para. 3. Retrieved October 30, 2020, from 

https://www.appliedclinicaltrialsonline.com/view/va-gets-real-reform

Chastain DB, Osae SP, Henao-Martínez AF, Franco-Paredes C, Chastain JS, Young GN, et al. Racial Disproportionality in Covid Clinical Trials. The New England Journal of Medicine. 2020; 383(9) e59-e59. Retrieved October 30, 2020, from 

https://www.nejm.org/doi/full/10.1056/NEJMp2021971

Paulsen E, Practice-Based Clinical Trials: Benefits and Barriers. Duke Health. 2016. Retrieved October 30, 2020 from 

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Kaplan GA, Weaver R, Cloud B. Clinical Trials: Insights from the Inside. Applied Clinical Trials. 2020; para. 13. Retrieved October 30, 2020, from 

https://www.appliedclinicaltrialsonline.com/view/effect-covid-19-clinical-trials-insights-inside

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, Tufts Center for the Study of Drug Development

Articles

Comparing late-stage COVID-19 vaccine trials to historical practices.

Investigative Site Placement Practices to Support Operation Warp Speed

New drugs and biologics approved in 2018 signal an exceptional period of change and opportunity in global drug development. This past year, the FDA approved 59 novel small-molecule (NDAs) and large-molecule biologic (BLAs) therapies-the highest number in history (see chart below). 

	This is a remarkable achievement, particularly in light of the anemic number of annual approvals that we saw in the 2005 to 2010 period. At that time, several industry watchdogs and prognosticators cautioned that the industry had exhausted its ability to develop truly novel and innovative therapies. They could not have been more wrong.

	What is most notable about 2018’s approval volume is not only the scientific innovations that produced them, but also where they originated, how they were funded, and the operating models, services, and technology solutions that supported them throughout the R&D process.

	One revealing feature that sets the 2018 class of approvals apart is the fact that 73% were approved under “priority review” status, meaning they were recognized by the FDA as important, truly novel treatments warranting an accelerated regulatory process. They are therapies targeting medical conditions for which there is no available treatment on the market or they offer substantial improvement over current therapies, including a standard of care.

	One-third of all new approvals in 2018  are first-in-class offering a novel mechanism of action-a new way of treating a particular disease. This is another record achieved by last year’s approvals. They represent exciting, truly novel breakthrough therapies, including next-generation vaccines, new antibiotics for drug-resistant infections, combination therapies, nanomedicines, microbiome or bacteria-based treatments, and gene therapies. 

	Immunotherapies have been one of the leading headliners (e.g., checkpoint inhibitors, CAR-T therapies, and other adoptive cell transfer drugs) and they top the list of breakthrough therapies receiving approval.  The first immunotherapy was introduced less than a decade ago; there are now nearly 2,000 cancer immunotherapies in small and large animal studies and in human testing. And immunotherapies that have already been commercialized to treat one form of cancer are now pursuing and receiving regulatory approval to treat many other cancer-related diseases.

	In addition to novel therapies, the FDA also approved the use of a record number of already-marketed drugs to treat new disease conditions and to be offered in new formulations that are more effective, accessible, and/or convenient to patients.

	In addition to notable areas of scientific innovation, new 2018 drug and biologic approvals also reveal a major shift in the composition of the drug pipeline and in the types of companies sponsoring drug development activity. Historically, the majority of new drug approvals targeted increasingly crowded chronic diseases affecting large numbers of people. Nearly 60% of approved drugs today target rare diseases that represent very small markets relative to those for chronic disease-or blockbuster-therapies.

	More than one-quarter (27%) of all new approvals are precision medicines. They rely on biomarker and genetic data to identify a far more targeted patient subpopulation that has a much higher likelihood of responding to a new treatment safely and effectively. According to the Tufts Center for the Study of Drug Development (Tufts CSDD), half of all drugs in the overall R&D pipeline-and about 80% of all drugs in development for cancer-related diseases specifically-now rely on biomarker and genetic data to target therapeutic agents.

	And whereas new approvals were historically dominated by the largest, top 50 pharmaceutical and biotechnology companies, today the majority of approvals are for drugs in development programs sponsored by small companies-many that are funded by private equity and venture capital. Sixty-percent of new approvals were from sponsors submitting their very first application to the FDA. This, too, is a record achievement.

	Small companies have unique needs, including a heavy reliance on outsourcing to support discovery, preclinical, and development activity; a proclivity to seek more open collaboration and data sharing models; and far more limited resources.

	In 2018, approximately $150 billion was spent on global R&D activity. Tufts CSDD estimates that R&D spending has been rising 6% annually since 2000. Nearly nine out of 10 drugs entering clinical testing fail, with wide variation in failure rates across different disease conditions. Investigational cancer treatment failure rates are among the highest. Drug development processes are highly complex and inefficient, with durations that have shown little to no improvement in more than three decades. And, on average, the typical drug generates a relatively low and declining return on its development investment, given the high capitalized cost-now estimated at $2.6 billion-to successfully bring a single drug through FDA approval.

	To remain viable, drug developers must transform long-standing R&D operating processes and practices that are largely insular and sequential, supported by redundant resources and personnel and that underutilize key assets and expertise. The growing prominence of precision medicines and treatments for rare diseases and targeted patient subpopulations-all requiring more complex clinical trial designs and longer durations to identify and recruit patients-intensify the pressure on drug developers to accelerate this transformation.

	Another revealing quality of the graduating 2018 class of NDAs and BLAs is that some are part of an emerging new paradigm that holds promise in delivering better quality, speed, and efficiency at lower cost. According to the Economist Intelligence Unit (EIU), during the past five years, an estimated 3% to 5% of clinical trials were “patient centric,” in that they included patients in clinical trial planning and design and they were executed with approaches that supported greater participation convenience (e.g., use of mobile technologies, transportation assistance, home- and work-based participation). The EIU found that patient-centric clinical trials had Phase II and III enrollment rates that were 40% faster. They also noted that drugs approved with patient-centric clinical trials had higher success rates and a greater likelihood of receiving formulary approval by insurers. Although the numbers are small at this time, we anticipate having more data on approvals in the coming years to further demonstrate the impact of this new operating paradigm.

	A growing number of new approvals are also being developed in an environment that favors more open, precompetitive data and information-sharing. New approvals also favor increasing use of external collaborations and service providers that offer scientific and operating expertise and operating advantages, smarter use of resources, and greater leverage of data and analytics to inform, manage, correct, and predict.

	During the past several years, we have seen massive investments by traditional R&D players and new entrants, consortia, the capital markets, and the public sector in data and data management capabilities and technology solutions and applications.  There is an enormous appetite currently for more sophisticated analytics, including machine learning and natural language processing to analyze a much higher volume of data from diverse sources (including clinical data and real-world evidence such as electronic health and medical records); to prioritize and target resources; to identify and interpret data patterns; to assess and mitigate risk; to manage complex logistical and manufacturing processes; to benchmark practices and, increasingly, to predict scientific and operating outcomes and performance.

	Patients and patient advocacy groups are playing a growing role in helping to direct and even fund drug development programs, to define clinically meaningful outcomes, and to push the scientific community to provide higher levels of relevance, convenience, flexibility, and transparency. 

	We are getting closer to being able to aggregate and look at data across the entire R&D and commercialization continuum. Components of an historically fragmented and disaggregated system within drug development and within the broader healthcare arena are becoming increasingly connected and integrated to share and make better use of scientific and operating data to support open and collaborative learning-what the National Academy of Sciences calls a Learning Health System-where every response a patient has with a commercially-available or investigational therapy informs personalized treatment as well as public health outcomes. As integration unfolds, we expect clinical research and clinical care to converge to drive efficiency through the removal of intermediaries and redundant fixed infrastructure and labor-intensive activity. And we expect patients, payers, and providers to play active roles in the development of new treatments.

	We have a long way to go to realize the full promise of this new operating environment and to navigate critical issues like data ownership, data privacy, data compatibility, and the gleaning and refereeing of insights in the data. But, as we revel in 2018’s new drug and biologic approvals, we are already seeing truly novel scientific innovations generated by a changing community of sponsor companies piloting and operating under an evolving drug development paradigm.

	There are now more than 11,000 active molecules in the R&D pipeline-a 5-7% year-over-year rate of growth across the span of two decades-to address unmet medical needs and improve patients’ lives. This is indeed an unprecedented moment.

, MBA, is the Director of Sponsored Research at the Tufts CSDD and Chairman of CISCRP, both based in Boston, MA. email: 

Record numbers point to new R&D operating environment, driven by a changing community of sponsors.

Reveling in 2018's Revealing Drug and Biologic Approvals

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

	Patients and the public are demanding higher levels of transparency and disclosure in clinical trials. And the 

National Institutes of Health (NIH), other government agencies, and most pharmaceutical and biotechnology companies agree that the return of plain language clinical trial results summaries is the right and ethical thing to do. But, despite broad consensus around this important issue, at the present time only 2% of all clinical trials completed or terminated within the past three years have returned their results-in plain language- to their respective study volunteers. 

	There are a number of perceived barriers preventing most companies from piloting and/or establishing processes to return plain language summaries. Most of these barriers have already been addressed, however. Regulatory pressure mandating the return of plain language summaries is also intensifying. It is clear that government and industry research sponsors alike will place greater urgency and effort into establishing and standardizing plain language results communication practices over the next 18 months.

	Articles in the peer-review and trade press-and anecdotal conversations that I’ve had with clinical teams, medical writers, and disclosure personnel through my involvement at the Center for Information on Clinical Research Participation (CISCRP)-highlight five perceived barriers to adopting plain language summary disclosure programs. They are:

		Uncertainty around resource requirements necessary to support plain language summary programs.

		Uncertainty about the cost to implement a plain language summary program.

		Uncertainty about how to best reach patients with relevant and useful summary information.

		Fear of liability from disclosing competitively sensitive and promotional summary information.

		Low perceived incentive-positive or negative-compelling compliance.

	These barriers have largely been addressed by research sponsors who are already voluntarily returning their clinical trial results summaries to patients. During the past eight years, CISCRP has worked with most of these commercial and non-commercial research sponsors to develop templates, operating processes, and standard practices. Frameworks and guidelines from organizations including TransCelerate, Clinical Trials Transformation Initiative (CTTI), and Multi-Regional Clinical Trials (MRCT) Center have also been created to help sponsors navigate uncertainty and establish practices.

	Research sponsors have found, for example, that medical writing and disclosure functions can share resources and personnel to support plain language summary projects. Staffing depends on the volume of clinical trial activity in the portfolio. A few research sponsors have established capability in-house to create plain language summaries, while others are outsourcing this responsibility to contract services vendors. Performing this activity internally or under contract with for-profit medical writing services may be problematic, though. These relationships can be unduly influenced by the research sponsor’s unintentional, or intentional, efforts to publish plain language summaries containing biased or promotional information. This is especially true of for-profit medical writing providers with well-established, longstanding preferred provider agreements.

	Implementation costs are relatively low and most sponsors are generally able to locate funds for pilot programs. But, due to delayed efforts for establishing which function will own the activity, continuity in funding for ongoing efforts is limited. Costs are highly dependent on the size and scope of each clinical trial and the number of translations (e.g., number of global investigative sites, number of study volunteers). With respect to the latter, typically research sponsors match the languages used in the informed consent form with those in plain language summaries. Once a plain language clinical trials results communication program has been established and begins to scale, however, process efficiencies help to lower the overall cost per program.

	Production and distribution costs have also been raised as concerns. Plain language summaries are typically returned to study volunteers through the investigative site; study staff send printed reports using mail-ready envelopes. A few research sponsors have been testing the distribution of digital formats, including pdf, simple data files, and html, through online portals. However, some sponsors are concerned about compromising the study volunteer-study staff relationship and they have been reluctant to move away from print distribution.

	Ethical review committees review and approve informed consent language, which typically includes notification to study volunteers that they will be receiving the results of their clinical trial. Ethical review committees also review any communications associated with the return of summaries provided to study volunteers while the clinical trial is underway (e.g., reminders and “Thank You” notes).

	To avoid the risk of bias and promotional summary language, and to ensure that patient and public needs are met, CISCRP (an independent non-profit) convenes an objective and neutral editorial panel of patients, patient advocates, medical professionals, and consumer health communication experts. This is done for every new plain language summary.

	Following receipt of the plain language summary report, most patients choose to review it with their primary or specialty care physician. It is rare that investigative site personnel are contacted to review the summary report one or more years after the clinical trial has ended. In those instances when site staff are consulted, reported time commitments average 30 minutes or less.

Regulatory issues and return on engagement

	The ethical obligation to return clinical trial results summaries to patients in “accessible” language can be traced back to the 1964 Declaration of Helsinki. Some 33 years later, in 1997, the Food and Drug Administration (FDA) Modernization Act led to the creation of a government maintained 

 for listing later-stage interventional studies for serious and life-threatening illnesses. Then, in 2007, the FDA Amendments Act (FDAAA) mandated that later-stage efficacy studies and approved products report clinical trial results within one year after the completion of data collection or study termination for later-stage efficacy studies and for approved products. The law also established a provisional monetary penalty of $10,000 per day (for industry-funded studies) and the loss of grant support (for NIH-funded studies) for failing to comply.

	In 2010, Congress signed the Plain Writing Act into law requiring federal agencies, including the NIH, to provide all communications to the public in plain, understandable language.

	In 2017 the FDA Amendment Act Title VII Final Rule was issued to clarify the registration process and regulatory requirement for submitting clinical trial results information, to expand the definition of applicable experimental treatments falling under the mandate, and to require plain language communication of information contained in the informed consent document.

	The European Commission established the European Clinical Trials Database (EuDRACT) in 2001. Eleven years later, the Commission issued Eudralex Volume 10 Guideline 2012/C 302/03, which required technical results summaries for all clinical trials conducted by at least one European member state to be posted on the 

 databank within one year after completion.

	In 2014 the European Commission issued Regulation 536/2014, reinforced by the European Medicines Agency’s (EMA) Regulation 007, to clarify the posting process on a new platform (EU Clinical Trials Register), expand the definition of trials to be registered, and to require that summaries be written in lay- or plain language. This most recent regulation is expected to go into effect toward the end of 2019 or in early 2020.

	With respect to return on engagement initiatives, several published studies suggest that higher levels of patient engagement are achieved when study volunteers receive plain language clinical trial summaries. A 2018 Tufts Center for the Study of Drug Development (CSDD)–Drug Information Association (DIA) study found that the return of plain language summaries is among a small set of patient engagement initiatives that offer a measurable return on investment due to their relatively low cost and positive impact on study volunteer experience and retention rates. And a 2017 study by CTTI, with support from Tufts CSDD, found that improvements in recruitment and retention due to patient engagement initiatives, including the return of plain language results summaries, significantly increased the expected net present value of a clinical program.

	In a global survey among more than 12,000 patients, CISCRP found that the promise to return a general clinical trial results summary is among the top five most important factors influencing a study volunteer’s decision to participate. And among 2,194 clinical trial volunteers who had completed their participation, the return of plain language results summaries had a positive, statistically significant impact on their perceptions, experiences, and overall satisfaction.

	Although research sponsors are piloting initiatives and a small number are implementing broader programs, the ethical obligation to return plain language clinical trial results summaries to study volunteers is not embraced by the clinical research enterprise. Overall low levels of support and adoption reflect poorly on the enterprise as a whole, harm efforts to engage patients as partners in the clinical research process, and raise public and patient concern and mistrust in the research professional community.

A growing number of commercial and non-commercial sponsors will increase their efforts to return plain language results in anticipation and preparation of mandates and their enforcement.

	Regulation requiring government agency support is already in place but requires harder deadlines and incentives to facilitate more rapid adoption. EU and North American regulation of pharmaceutical and biotechnology companies is tightening and enforcement may become more commonplace. Industry reputation is also tenuous in the current political environment made worse recently by widespread price increases of marketed drugs.

	It is in the clinical research enterprise’s best interest to support initiatives that strengthen its relationships with patient communities and the public. The return of plain language summaries reassures patients that sponsors intend to be fully transparent, regardless of the study outcome, and is an important way to demonstrate a commitment to these valuable and highly valued partnerships.

It’s time to establish standard practices to return clinical trial results summaries to patients.

Kenneth Getz

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