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Applied Clinical Trials June 2022

ACT's biennial Salary Survey takes a look at the future of industry following increased adaptation of decentralized technology 

Salary Survey: The Age of COVID

Emerging tools in data analytics, automation, EMR aggregation, and even social media are enabling faster and easier patient recruitment

Patient Recruitment Goes High-Tech

 based on “sensitive data” related to their health condition, it might have been easy to conclude that the social media giant would stifle drug development research as a result. While Facebook is just one example of social media used by clinical trials to recruit patients, we would estimate that Facebook accounts for roughly half of all direct-to-patient recruited participants for a given trial, based on our observations from running global patient recruitment campaigns in the past few years.

The truth, however, is that Facebook’s ban, which went into effect in January, is not a setback.

The ban should push clinical research to accelerate more patient-centric advertising models that enable privacy while ideally improving public health by increasing access to clinical trials.

Digital advertising for clinical trials should be about getting potentially life-saving drugs to market more effectively, not broadly targeting anyone who’s visited a cancer charity website for an oncology study. This kind of wide-net casting is not nearly as effective as most believe. The future of healthcare and clinical research advertising depends on our ability to create greater impact by analyzing underlying data. The way to get there is through patient-centric advertising models.

Traditional digital advertising challenges

For decades, digital advertising has been part of clinical researchers’ playbooks to supplement the pool of patients available to investigators. However, these traditional approaches have been far from successful. They often result in extensive, burdensome screening activities only for the sites to enroll a few more patients.

More traditional interest advertising (based on interest in products or topics) and predatory advertising models are much more likely to lead to a poor outcome for underrepresented groups of patients, especially when clinical researchers rely solely on Facebook’s native targeting tools.

Shifting gears is not so easy. It’s a new frontier for data privacy, especially as high-profile breaches dominate cybersecurity news. Gone are the days of the third-party cookie. In 2022, addressing privacy concerns is a must, and that is where the Facebook ad ban is rooted.

Many consumer brands are taking steps to make consumers more comfortable about their privacy during online activities. When it comes to clinical research, the end goal is to inform and benefit as many patients as possible, not sell.

Many digital recruitment companies are adjusting. Despite how specific an advertisement may seem, digital recruitment companies do not need to know any personal patient information when they are seeking to draw in potentially eligible candidates. In fact, no personal information is known until the patients themselves opt into the enrollment process.

Ultimately, this kind of patient-centric advertising calls for a more personalized experience for users by explaining why particular ads were directed toward them. In a world in which the internet is more and more dominant in our daily lives, it’s essential to continue using it as a tool to drive improved success rates of clinical trials.

Thanks to the acceleration of data and cloud adoption, those in charge of trial recruitment and enrollment can employ tools and solutions that allow them to better target audiences more likely to fit their studies’ eligibility criteria.

Newer sophisticated digital marketing approaches utilize different platforms such as Google, Amazon, Taboola, and others to push ads to thousands of other web pages and millions of people, then take note of respondents and utilize the resulting information as a learning loop into audience modeling. It’s also possible to feed these learnings into Facebook’s modeling, which boosts advertising effectiveness on the platform. Qualified patients can then access clinical recruitment information without having their sensitive personal data misappropriated to target them.

Patient-centric, smart modeling techniques expand the pool of potential clinical trial participants and then narrows down the pool to only the most relevant candidates matching the study criteria. These models start with initial patient personas, developed from large RWD repositories, and then continuously refine themselves based on engagement. This adaptive, hyper targeting approach provides sites with a steady flow of motivated and study-ready patients and allows them to focus on the final clinical evaluation prior to enrollment.

This is not the time to lament Facebook’s decision. Instead, the ad ban represents an opportunity to begin a conversation between the pharma industry and social media channels. RWD and analytics provide solutions for some of the most long-standing barriers to clinical research studies, but must be truly patient-centric and used responsibly.

Articles

In light of Facebook ban on ads targeting patients, industry has chance to reinvent digital advertising for trials.

How to Improve Recruitment Rates, Reduce Site Burden, and Avoid Wasted Spending

On July 25, the American Society of Clinical Oncology (ASCO) and the Association of Community Cancer Centers (ACCC) jointly released resources to help research sites increase the racial and ethnic equity, diversity, and inclusion (EDI) in cancer clinical trials.

™ Training Program and Site Self-Assessment represent a full and complementary set of resources that can help research sites address barriers to participation in cancer clinical trials among racial and ethnic populations that have been historically underrepresented.

Organizations jointly release resources to help research sites increase racial and ethnic equity, diversity, and inclusion in cancer trials.

American Society of Clinical Oncology (ASCO) and the Association of Community Cancer Centers (ACCC) Announce New Initiative

Jill Wechsler is ACT's Washington Correspondent

Amidst a host of serious challenges for maintaining FDA operations and programs, Commissioner Robert Califf is most determined to combat erroneous reports about medical treatments and clinical practice. “Misinformation is the leading cause of death in the United States today,” Califf stated at an online briefing sponsored by the Alliance for Health Policy on July 28. He noted that a poor understanding of the effects of medical treatments “leads people to make decisions that are harmful to health.”

Unfortunately, Califf fears that FDA is “actually losing the battle on misinformation” related to COVID, as seen in the large number of Americans who have not been vaccinated,” he observed in a conversation with the editor of 

 yesterday. Millions of people are refusing vaccines and therapies despite evidence that such treatments can reduce the risk of dying from the disease by 90%. “Vaccines are basically working,” Califf stated, yet he sees many people who won’t take a treatment that’s free and highly effective.

Califf hopes to address this conundrum with a strategy for dealing with the “avalanche of differing opinions” that is confusing and difficult for Americans to navigate. This cardiologist recalls such problems throughout his career, as experts failed to reach agreement on treatment strategies for critical conditions. And today, when FDA makes a regulatory decision, it draws comments from all corners of the world, he notes, which ends up providing the public with a “sea of information” that’s difficult to navigate.

Califf’s response is to establish a “better evidence-generation system” in the US, with expert networks devoted to developing reliable information and to checking facts to overcome misleading statements. He recognizes that there is a highly effective clinical trial system in the US, where preapproval studies produce needed data on product safety and effectiveness. But problems arise in postapproval confirmatory studies, where answers can take years, even decades, to emerge. To gain needed evidence, Califf would like to see clinical trials embedded in care and utilizing information systems that can tap larger samples of patients to answer questions very quickly.

Clinical research has experienced some success becoming more diverse in several ways, Califf believes, as seen in “tremendous progress” in including children in research, a group that he saw completely left out of clinical trials in the past. He would like to see similar gains in bringing research to rural America, where inadequate health care has reduced life expectancy notably. Califf would like clinical research to address disparities between urban and rural areas, as well as differing treatment responses of ethnic and racial populations.

A continuing challenge for FDA is the use of expedited clinical research approaches to accelerate the development and approval of treatments for lethal and rare diseases. The agency’s accelerated approval pathway has raised questions about abbreviated testing methods and chronic delays in follow-on trials. Califf indicated that while abbreviated, single-arm trials may be appropriate for testing new therapies for untreated cancers and rare diseases, randomized trials with proper controls may be more acceptable in providing evidence for treating conditions with approved therapies.

In addition to addressing the harmful effects of medical misinformation, Califf faces a host of regulatory and policy crises across the board. Not the least is the looming loss of funding due to delays in Congress reauthorizing user fees and a new budget for 2023.

In addition, a broad overhaul of the agency’s oversight of tobacco and related products is a top priority. With 30 million Americans still using tobacco, plus a rise in vaping products, Califf sees FDA entering a new era in tobacco product oversight, with key decisions looming on menthol cigarettes and reduced-nicotine products. Califf anticipates “major disagreements” no matter what FDA does, but hopes that transparent communications will build support.

Opioid addiction remains a critical challenge. Califf seeks new strategies for providing education and oversight of prescribing and access to regulated opioids, while also dealing with a huge increase in illegal high-dose fentanyl pills sent through the mail. FDA is preparing a plan for more collaborative approaches to address these issues, but Califf recognizes there is “no magic bullet” for dealing with this ongoing national crisis.

Califf also has launched a broad review of food oversight and regulation by the agency, spurred in part by the recent infant formula crisis. FDA seeks better funding and improved hiring authority for its food programs, as well as a broader assessment of the impact of changes in how food is grown and distributed in the US. And the sudden drop in infant formula supplies has highlighted the need to diversify sources and increase US production of such critical products.

Califf observed during these briefings that when he decided to return to FDA for another stint as commissioner, he anticipated there would be very serious challenges, but not as many as have erupted. But he re-upped for the job because he also recognized that heading FDA would “take someone with not much at stake.” His long experience overseeing clinical trials has made clear to him the importance of good evidence and strong collaboration in organizing programs and making sound decisions, and he continues to work to apply such approaches to the complexities and diversity of FDA.

Better clinical data needed, as well as strategies for tackling opioid abuse, tobacco use, and food safety.

Top Priority for Califf is Combating Health Misinformation 

H1 and Lokavant announced a data-and-analytics collaboration to bring enhanced automated intelligence to drug development. As part of the bi-directional partnership, Lokavant will provide performance data on global trial sites and principal investigators to supplement H1’s existing Trial Landscape clinical trial repository.

Lokavant will provide performance data on global trial sites and principal investigators.

H1 and Lokavant Announce Partnership

As the clinical trials industry prepares for the final FDA guidelines on real-world data,* executives must consider how their organizations should invest in real-world data going forward.

 The COVID-19 pandemic has illustrated both the benefits and drawbacks of real-world data, accentuating the need for more information about how organizations should invest in these capabilities.

The decision to invest in real-world data is complex. Enthusiasts point to the benefits of real-world data, including the availability, efficiency, and generalizability.

 Skeptics of real-world data counter with the still uncertain regulatory environment and cite concerns about the quality, validity, reliability, relevance, costs, and provenance of the data.

 At the same time, the stakes are getting higher on these real-world data investment decisions; data is getting more expensive to acquire, curate, and protect.+ Achieving a positive return-on-data in this environment demands multi-functional collaboration on the use of the data across silos.

The first purpose of this research is to describe the overall current and future usage of real-world data. Real-world data usage is assessed within each of the functional areas (e.g. corporate strategy, trial design, site selection, or FDA submission) and then averaged into an overall usage score to get a view of how real-world data is being used across silos. We then examine the factors that drive real world data usage in two areas—the actual data as well as the data intermediaries/software providing that generate information from the data. The results of this analysis will help clinical trials make rational investments in real-world data.

We conducted descriptive research with purposive sampling of pharmaceutical and CRO executives. We solicited participation from readers of 

Respondents were incentivized with a chance to win one of five $20 Visa gift certificates. The survey had 16 questions with some of the subsections having multiple items (total items = 143), including demographic items such as the type of organization (e.g., CRO or sponsor), size of organization, seniority, and role (e.g. clinical or commercial). Since this is descriptive research, respondents were allowed to skip questions to enhance the reliability of responses. The data was collected in September to October 2021. Some of the data management was conducted in Excel 365, version 2111 and data analysis was performed in SAS 9.4.

Our estimation of real-world data usage is cross-functional. Rather than asking for global assessments of real-world data, we asked respondents to assess real-world data usage within specific functions (corporate strategy, R&D, clinical trial design, site selection for clinical trials, patient matching for clinical trials, synthetic control—nonregulatory grade, health economic/outcomes research, FDA submission—basis for approval, FDA submission—supportive, market access—payer negotiations, post-approval safety studies, and other post-approval research). We then averaged usage across these functional areas to estimate respondents’ overall assessments of real-world data usage.

We organized our analysis into three areas each having a pair of questions: current and future usage of real-world data; importance of raw data attributes and satisfaction with data attributes; and the importance of and satisfaction with the characteristics of data intermediaries—including analytic vendors or consultants and software—used to provide and interrogate the raw data and generate information. The data attributes that we included were the presence of retrospective and prospective longitudinal data as well as biomarker data, and the ability to tailor the data and data dictionary and do chart reviews. The attributes of data intermediaries/software included the ability of the software platform to enable analytics and allow evaluation as well as their cost, reliability, problem solving, flexibility, responsiveness, and understanding of needs.

For each of these areas, we examine the mean scores for each of the items and create difference scores between current and future usage; data attribute importance and satisfaction; and data intermediary/software importance and satisfaction. These difference scores are important because they represent the potential growth of real-world data in the current/future usage or opportunities to grow in the gaps between importance/satisfaction. All variables used in significance testing had acceptable normality and met the assumptions for that statistical test.

We had 133 responses after screening out respondents not in the sampling frame, abandoned surveys, or evidence of careless responding.

 The respondents came from a variety of types and sizes of organizations, seniority, and roles. Forty-two percent of the respondents worked at sponsors, 47% from CRO’s or functional service providers, and 11% from other (e.g. government agencies or non-profit advocacies). Thirty-seven percent of the respondents were from small companies (<100 employees), with 24% from medium sized companies (100-2,000 employees), and 38% from large companies (>2,000 employees). As for seniority, 24% of respondents were in the C-Suite, 10% were Vice Presidents, 29% were Directors, and 19% were managers. Finally, 47% of respondents had a clinical role, 32% had a commercial role, and 19% worked in a corporate role.

Current and future usage of real-world data

The average current usage of real-world data was a 5.8 on a range from 1 to 10. We found this to be a modest usage rating given the enthusiasm and amount of time real-world data has been available from EMRs. Current usage varied significantly (F2,116= 11.06, p< .001) by the type of organization, with CRO’s (μ= 6.8) having greater usage of real-world data than sponsors (μ= 6.0) or others (μ= 5.0). There was not a significant (F4,116= .88, p= .48) variation in the usage of real-world data based on the size of the organization or by the respondent’s role (F2,114= 1.31, p= .27) within the organization (i.e. clinical, commercial, or corporate). The functional area ratings for current usage are shown in the solid columns of Figure 1. The functional areas with the greatest current usage of real-world data were health economics and outcomes (μ= 6.8), post-approval safety (μ= 6.4), clinical trial design (μ= 6.4), and market access (μ= 6.3). Even within the functional areas with the highest usage, we still found these usage ratings to be relatively mediocre. The area with the lowest area of usage was non-regulatory synthetic control (μ= 4.4).

 Current and future usage of real-world data broken out by function. The solid columns are current usage and the pattern-filled columns are future usage.

The anticipated future usage of real-world data was 6.4, or just 0.6 points higher than current usage, suggesting that respondents anticipated modest future usage of real-world data across all the functions. The future usage ratings are shown in the pattern-filled columns of Figure 1 above. There was no variation in future usage based on the size of the organization (F4,116= .78, p= .54) or the respondent’s role (F2,114= 1.31, p= .27) but there was significant variation based on the type of organization (F2,118= 8.16, p= .005), with CROs (μ= 7.2) anticipating greater future usage of real-world data compared to Sponsors (μ= 6.7) or the group of Others (μ= 5.3). The future usage ratings within each of the functions were similar to the current usage, with Health Economics/ Outcomes (μ= 7.2), Post-Approval Safety (μ= 6.9), and Market Access (μ= 6.7) having the greatest future usage and Synthetic Control (μ= 5.2) having the lowest future usage.

The differences between current and future usage ratings provide insights on the potential growth of real-world data and are shown in the line graph of Figure 1. All of the differences were quite small, with average of all the differences being .6 on a 1 to 10 scale. One perspective could be that these relatively small differences suggest limited growth for real-world data. The greatest opportunities for real-world data growth were in the areas of corporate strategy (Δ= .86) and supportive FDA submissions (Δ= .85), as shown in Figure 3.

We next focused on the characteristics of the raw data that drove the adoption of real-world data, looking at the importance of the data characteristics first. The overall importance of the data characteristics was a mean of 7.3 on a scale of 1 to 10. There were no significant differences based on the type of organization (F2,129= 2.02, p= .13), size of the organization (F4,127= 1.24, p= .30), seniority (F4,127= .15, p= .96), or role (F2,127= .54, p= .58). The scores for the specific functional areas covered a fairly narrow range of .8, suggesting that the specific characteristics are either relatively equal or difficult to evaluate to these executives. The importance ratings for the various functional areas are shown in the solid columns of Figure 2 below. The most important attributes were the presence of retrospective and prospective longitudinal data, analytics support, and the ability to tailor the data, also shown below in Figure 2.

 Data attribute importance and satisfaction ratings broken out by data attribute. Solid columns are the importance ratings. Pattern-filled columns are the satisfaction ratings. The average difference between importance and satisfaction was -1.2.

The overall satisfaction with the data attributes was 6.1 (Range 1 – 10), compared to the mean of 7.3 for the importance of these attributes. Satisfaction with the raw data was .9 of a point (on a scale of 1 to 10) below importance, suggesting an opportunity for improvement in the raw-data attributes. There were no differences based on the type of organization (F2,73= 2.68, p= .08), size of the organization (F2,71= .43, p= .78), seniority (F4,71= .40, p= .80), or role (F2,72= .99, p= .37). It is interesting to see the drop-off in responses to this section, as can be seen in the second number in the degrees of freedom. We did not force completion of any responses, so this drop-off suggests that our respondents felt less qualified to evaluate the data attributes. Within the specific attributes, satisfaction was highest on tailoring the data, the availability of retrospective and prospective data but struggled the most with chart reviews and biomarker data, as shown in the pattern-filled column of Figure 2.

We again compared the difference between the importance of data characteristics and satisfaction. These difference scores provide insights on how to improve usage of real-world data. The average difference between the rated importance of the various data attributes and The line graph in Figure 2 shows the difference between the rated importance and satisfaction for each of the attributes. None of the data attributes had satisfaction scores that were above the rated illustrating the gap between satisfaction and importance.

The area we considered as a driver of real-world data usage focused on the data intermediaries/software platforms that enable access to the data. The overall mean for the importance of data intermediary/software attributes was 7.9, which was higher than the overall mean for the data attributes (μ= 7.3). There were no differences in importance based on the type of organization (F2,128= .35, p= .70), size of organizations (F4,126= 1.0, p= .41), seniority (F2,126= .58, p= .68), or role (F2,126= 1.41, p= .26). The functional breakouts for the data intermediaries/software are shown in the solid columns for Figure 3. Note the higher degrees of freedom from the higher response rate, suggesting these executives found it easier to evaluate the data/software intermediaries.

 Data Intermediary/ Software attributes. The importance ratings are in the solid column and the software rates are in the pattern-filled column.

The satisfaction with the data/software attributes was 6.4, quite a bit less than the importance average of 7.9. There were no differences seen for type of organization (F2,125= 1.55, p= .22), size of organization (F2,123= .98, p= .42), seniority (F2,123= .26, p= .90), or role (F2,123= 1.37, p= .26). The satisfaction of the data intermediaries/ software attributes are shown in the pattern-filled columns of Figure 3 above.

The difference between the attribute importance and the satisfaction illustrates the potential for improving real-world data adoption/usage by narrowing this gap. Software platforms had the highest gap (μ= 1.5), suggesting a greater opportunity for growth in real-world data usage compared to data (μ= 1.0). The greatest differences (or opportunity for growth) were seen in the intermediary/software reliability, cost, responsiveness, and understanding of needs.

Current usage of real-world data was mediocre (μ= 5.8) across all functional areas but was highest for health economics/outcomes research, post-approval safety studies, and clinical trial design.

Anticipated future usage of real-world data (μ= 6.4) was slightly higher, with the greatest growth opportunities in corporate strategy, supportive FDA submission, and synthetic control. FDA approval came in a distant fourth.

The importance of the software platforms (μ= 7.9) was rated as being more importance that the actual data (μ= 7.3).

The greatest opportunities to improve real-world data usage came in the area of data/intermediaries/software platforms.

Intermediaries/software was rated as being more important,

The difference between the importance and satisfaction was greater for the software platforms (Δ= -1.5) than for data (Δ= -1.1), suggesting a greater opportunity for growth.

The prominence of real-world data grew rapidly from the publicity and success of its use during the COVID pandemic, the update to the FDA guidance, and a global market expected to grow at 14.4% (MarketsandMarkets, 2022). The results of this study temper that enthusiasm by demonstrating that overall real-world data usage and perception of its value is at mediocre levels with limited potential for growth seen by industry executives. The satisfaction gap with both raw data attributes and the intermediaries/software options are perhaps more of a concern. Part of this satisfaction gap may result from higher expectations related to the effort and money necessary to create real-world datasets now.* For those interested in achieving greater usage of real-world data, our results suggest focusing on the intermediaries and, in particular, the software that interrogate the raw data to generate information.

The findings on mediocre usage of real-world data align with the 2017 Deloitte survey demonstrating about half of companies are investing in real-world data. Our research extends this finding by examining usage across functions. These usage findings also align with the challenges that health care providers and the general business community are having with using real-world data in health services (Goo, Huang, & Koo, 2015; Howley, Chou, Hansen, & Dalrymple, 2015). As a CEO once told the second author, “I get the importance of data systems and I am willing to write large checks for them. But I have been disappointed in the return in those investments.” (Baynham, 2005). Viewed from this lens, then, the usage findings may suggest that real-world data in the clinical trials is performing at an above-average level.

These return-on-data dynamics are at the core of this analysis. On one hand, acquiring and curating data is now a centralized function of the organization that has become very expensive. This has sharply increased the denominator for any return-on-data calculations.* Organizations must improve their return-on-data by using data across more functions.. Different areas still have different data requirements and standards, but different functions are becoming more open to extracting information from the centralized data. To improve the numerator of the return-on-data calculations.

The results of this research suggest limited growth for real-world data usage absent meaningful changes to practical aspects associated with its use. The anticipated future usage was less than 1-point higher than current usage. We recognize this contrasts with expected market growth of 14% annually.

 In part, this may reflect the differential between the quantity of use and the anticipated cost of obtaining and working with the data. For example, executives we spoke to about these results point to the complexities of curating the data. Acquiring a large dataset is one thing, but wrapping that data in an ecosystem that makes that data usable is a more difficult challenge.+ The challenge today for real-world data is how to create that ecosystem to extract the value from the data.

In summary, we see the path forward for real-world data pivoting on three issues. First, the industry must continue to build a business case for real-world data beyond FDA approval across the other functions. The value of its use in R&D strategy, protocol development, clinical trial participation, HEOR, and commercialization is increasingly clear. However, the future for RWD as a primary basis for FDA approval based on real-world is significantly less established and remains unclear. Nonetheless, progress is being made as the FDA continues to accept real world-evidence based on RWD as supportive and supplemental to submissions.

Second, can the quality of the data be maintained and standardized across all functions, which have different data requirements, and often source data independently (though there are indications that is beginning to change). While this evolution must continue, the data must maintain the required validity and reliability across all applications.

Third, as large and integrated data sets become the norm, development of low-code or no-code tools by which managers can interrogate the data and yield reliable insights is critical. Otherwise, the utility of the data is significantly reduced if the ability to analyze and interrogate it becomes too burdensome. As real-world data spreads across the functions, can we accommodate a variety of data analytic skills?

Last, data providers must examine the low-scoring aspects of their offerings to determine how better their customers can be served beyond just continuing to improve overall data quality. The breadth of dissatisfaction is too great to leave unaddressed.

The limitations of this study should be kept in mind in interpreting these results. Our approach to assessing overall real-world data usage by averaging across functions is different and potentially could skew to the downside. On the other hand, this provides a unique perspective on the breadth of real-world data usage and not just the depth. For real-world data to have a meaningful impact on clinical trials, it should be used across multiple functions. This is a cross-sectional online sample of executives, which could result in bias. We attempted to offset this as much as possible with a careful careless responding analysis. This survey also takes place at a specific context and point-in-time. We believe, however, that this is a propitious time to understand the industry sentiment of real-world data. Finally, the organizations we sampled used real-world data across multiple therapeutic areas. This is becoming increasingly common+ as these datasets become more expensive. Future researchers interested in the influence of therapeutic area should consider the role of organizational capabilities on real-world data usage.

Although real-world data enjoys broad enthusiasm, the decision for companies on whether and how to invest in real-world data is complex and ambiguous. This research provides a context for these decisions by showing how real-world data is being used across the clinical trials industry. We find that real-world data usage is at mediocre levels with limited potential for growth. The path to greater uptake of real-world data is through the data intermediaries/software, which are seen as more important than the actual data and have a greater discrepancy between the rated importance and satisfaction. Focusing on the data intermediaries/software should allow for greater adoption of real-world data and greater breadth of usage across the functions.

Author’s Notes: 1) Both authors contributed equally in the creation of this manuscript. 2) We are grateful to the participants of the 

 participants who discussed these issues with us on March 10, 2022 and the other clinical trials executives who provided insights into our findings. Their contributions are denoted with a + in the manuscript.

*In this paper, we consider the terms ‘real-world data’ and ‘real-world evidence’ to be equivalent constructs.

, PA-C, MBA, PhD, Clinical Professor, LeBow College of Business, Drexel University, 

, MBA, Senior Director, Market Development, Phreesia, Inc.

Considerations for the Use of Real-World Data and Real-World Evidence To Support Regulatory Decision-Making for Drug and Biological Products: Draft Guidance for Industry

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/considerations-use-real-world-data-and-real-world-evidence-support-regulatory-decision-making-drug

Nazha, B., Yang, J. C., & Owonikoko, T. K. (2021). Benefits and limitations of real-world evidence: lessons from EGFR mutation-positive non-small-cell lung cancer. 

Pearson, R. M. (2021, November 12, 2021). Real-world data on the safety of covid shots for young children is just weeks away.

https://www.washingtonpost.com/opinions/2021/11/12/real-world-data-safety-covid-shots-young-children-is-just-weeks-away/

Rudrapatna, V. A., & Butte, A. J. (2020). Opportunities and challenges in using real-world data for health care. 

The Journal of Clinical Investigation, 130

Sherman, R. E., Anderson, S. A., Dal Pan, G. J., Gray, G. W., Gross, T., Hunter, N. L., . . . Robb, M. A. (2016). Real-world evidence—what is it and what can it tell us? In (Vol. 375, pp. 2293-2297): Mass Medical Soc

Sundgren, M., Kaj Stenlöf MD, PhD, Lollo Eriksson, PhD, . (2021). Using Real-World Data in Patient Recruitment. 

Wechsler, J. (2021). FDA Acknowledges Hurdles in Utilizing Real World Data.

Meade, A. W., & Craig, S. B. (2012). Identifying careless responses in survey data. 

MarketsandMarkets. (2022). Real World Evidence/RWE Solutions Market by Component (Dataset (Claims, Clinical, Pharmacy, Patient), Services), Therapeutic Area (Oncology, Cardiovascular, Neurology), End User (Pharma, Medtech, Payers, Providers) Covid-19 Impact - Global Forecast to 2026. Retrieved from 

https://www.marketsandmarkets.com/Market-Reports/real-world-evidence-solution-market-76173991.html

Survey among readers evaluates the trajectory of RWD and how it can be more widely adopted.

Current and Future Use  of Real-World Data 

Industry Leader, TCS ADD™ Supply Management

The clinical trial supply space has many examples where current practices following traditional, conservative, historically proven, and perceived “safest” approaches to delivering medication to trial participants are being favored over newer alternatives that have become available. In recent months, regulatory bodies have provided guidance

 that could spur clinical trial supply-chain digitalization and innovation initiatives. This will enable life sciences industry to deliver the greatest benefits to trial participants at the receiving end and help unburden operational teams who support the process throughout.

The movement towards trial decentralization has accelerated since the pandemic. We’ve also observed a rise in medication tracking across complex direct-to-patient supply chains and remote medication adherence monitoring. Although signs have been encouraging with possibility of studies now being more inclusive, fragmented guidance on direct-to-patient home services and remote medication adherence monitoring have potentially limited its adoption.

In late 2021, FDA issued draft guidance on digital health technologies (DHTs).

The DHT draft guidance attempts to clarify the kinds of devices and software that may be used for remote monitoring of clinical trial participants to ensure that the data is sufficient to support a product application. While the draft guidance overall was well received, multiple questions and feedback arose mainly seeking to clarify what exactly is included and excluded from being a DHT to drive greater diversity and inclusion by providing digital solutions to non-traditional sites that are more difficult to access.

 FDA is yet to comment on responses to the clarification questions on what technology is included and excluded from DHT guidelines. Once known, products that have digital technology and approaches that operate outside FDA DHT guidance will undoubtedly face uncertainty; and the only real choice is to follow the guidelines and ensure they are compliant regardless unless they can justify why their technology is not in scope.

The FDA guidance on DHT helps trial sponsors to feel more confident on how and where technology can be used in trials for unit dose level adherence monitoring and provide insights into participant’s medication adherence. It also clarifies how wearables and devices, providing digital endpoints can be used in defining outcomes of a trial.

With this, many manufacturers of packaging products that monitor and support participant medication adherence are considering ways to re-augment their products from being described as SMART packaging to being DHT compliant in US trials (with potential for these to be used across global trials). This may be a strategy to build clinical and regulatory stakeholder confidence in the compliance and validity of the technology and benefits they bring. The adoption of this approach also allows electronic drug reconciliation to unit dose level in a pack. This potentially unburdens clinical site and monitoring staff to a large extent. The future looks promising for unit dose level tracking for medication adherence especially as decentralized trials continues its growth trajectory and expands the activities that are not delivered via the physical attendance of participants at investigator’s clinical site.

The new European Clinical Trial Regulation (Regulation (EU) No 536/2014)

came into force in January 2022 and the EMA forward looking plans complementing the regulation shift outlined in the Accelerating Clinical Trials in the EU (ACT EU) initiative came into action in early 2022. The regulation provisions use of a single portal to process clinical trials data across EU. While there are clear benefits to good clinical practices (GCPs) with a streamlined central portal and process re-engineering to a more centralized clinical trial application approach are compelling. The new EU Trial Regulation also introduced more challenging changes to the long established GMP processes. It outlines the principles and guidelines for good manufacturing practice for investigational medicinal products meant for human use and arrangements for inspections thereof.

 It includes minor changes such as rechristening of the term non-investigational products (NIMPs) to auxiliary medicinal products (AMPs) and the pre-fix Authorized and Un-authorized if the product has Marketing Authorization under the European Medicines Agency jurisdiction.

The most challenging changes are with expiry date management and label text requirements. Central systems like the randomization and trial supply management (RTSM) system are no longer allowed to manage expiry date alone and further to this, under Annex VI, expiry date must now appear both on the product’s inner primary and outer secondary packaging.

 This is particularly challenging given the rolling stability studies of the drugs as they are in clinical development. Consequently, expiry updates, traditionally performed only on the outer packs in distribution hubs and trial sites, will now be much more challenging. This new level of inner/primary container label expiry update makes it a higher risk activity outside the GMP facilities they were packaged in. Generally, the unblinded status of staff working in GMP packaging suites and the segregation procedures they have in place ensure minimal risk of mixing up of pack contents between different blinded medication packs as they are opened, re-labelled and then kits re-assembled and tamper sealed. 

Some time ago, The EFPIA and ISPE released a position paper providing options on how best to manage the supply chain complexities presented by the new Annex VI. This took a risk-based approach using trial pack re-design and expiry date process work arounds more aligned to traditional concepts of packaging trial medication and printed label expiry updating. There are forward looking suggestions from both parties that emerging trends and technologies like ‘Just in Time’ and e-labels may be options in the future.

Given the passage of time from these articles, this is the future and e-label are becoming available, but their development timeline has slowed due to the global pandemic and key enabling technology around displays and batteries restricting their market readiness. E-paper display entry into use in trials has also been restricted by interoperability issues of needing proprietary antenna and cradles for updating the labels across the trial network. That said, since late 2018, when Apple devices opened near field communication (NFC), app developers

 could design apps on both Android and Apple BYO devices that can theoretically update e-paper displays used as clinical trial medication labels. 

Role of technology in the scheme of things

Options for using Bluetooth low energy (BLE) or NFC help make the process more interoperable than ever before. The ability to update the expiry date on an e-paper display label containing all the regulatory required text applied to medication kits without the need to return them for re-package to a GMP facility, while eliminating multi-page booklet labels, is hugely compelling. It remains a requirement in Annex VI

 to have expiry dates and other items in human readable text physically on the packs. However, a digital copy of the most up to date label in a BYO device offers a convenient way to send updates to the e-paper display labels, on the product, and demonstrates a more patient centric label option to zoom and scroll in a participants preferred/approved language. While in app labels on BYO devices cannot replace the regulatory required text on the product label they can act as a digital supplement to drive patient engagement and protocol compliance.

Also in early 2022, the UK Government’s Medicines and Healthcare products Regulatory Agency (MHRA) and Health Research Authority (HRA) teams set out post-BREXIT proposals to re-define clinical trial regulation.

On a high level, it looks to remove obstacles to innovation, whilst maintaining robust oversight of safety of trials and ensuring the legislation builds international interoperability. This would eventually ensure that UK remains a preferred site to conduct multi-national trials. The running theme is to lower the burden of conducting low-risk trials across both areas of GMP and GCP and simplify things where possible. Proposals include requiring patient and public involvement in Research Ethics Committee review processes. To reduce barriers to participation, options to use a single front door for the Clinical Trial Application and Research Ethics Committee and a combined downstream review process (given the success of recent pilots) is vetoed. In addition, the proposal aims to simplify Informed Consent in cluster trials, reducing the burden of requirements for low intervention trial and as an alternative to the new EU Annex VI label regulations. The proposal also suggests that trials can be assessed as a risk-based approach to justify no physical re-labelling with trial information of some already commercially available medications being used in a protocol.

The option is to have medication management in a participant app to support kit level scanning of commercial bar codes and ensure the correct product is in the participants hands. This also presents an opportunity for participant apps with digital label or electronic packaging insert to support taking their trial medications correctly. Pilots of electronic product information using blockchain technology in the commercial supply chain are already under-way.

Recent updates by regulators on how trials can be conducted and how digital health technologies can support them have created more confidence of integrating them into future trials. The need to try harder to include population diversity and flexibly support traditional, decentralized, and hybrid-trial designs is also a key driver to digitalization. Avoiding overwhelming trial participants with the number of potential apps to be used is a key consideration. The appetite of participant to use BYOD devices for medication management has grown and scanning of QA codes on own devices has become a new normal for a while. This may be linked to the adoption of COVID apps.

In some ways the UK has shown an appetite towards a slightly broader set of innovations to the drug development and clinical trial processes, and most regulators are now paying attention to how digitally enabled and innovative trial processes can be conducted to maximum effect.

 More needs to be done to ensure data interoperability for global trials fully benefit from the digitalization opportunities we now have. There is a big push to use data from electronic health records alongside clinical trial data with electronic health record to trial electronic data capture platform (EHR to EDC) links now expanding. If this can be achieved along with ensuring participant’s medication adherence, using a combination of Real-World Data and Clinical Trials Data sources, it will strengthen trial outcomes and benefit new medications being provided to patients that are being treated.

PhD, Industry Leader, TCS ADD™ Supply Management

Digital Health Technologies for Remote Data Acquisition in Clinical Investigations. 2022. Available at: 

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/digital-health-technologies-remote-data-acquisition-clinical-investigations

REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC. (April 2014) Available at: 

https://ec.europa.eu/health/system/files/2016-11/reg_2014_536_en_0.pdf

Industry Stakeholders Respond to FDA’s Draft Digital Health Technology Guidance (2022) Available at: 

https://www.aardexgroup.com/2022/03/30/fda-dht-guidance/?utm_campaign=Quarterly%20Newsletter&utm_source=email&utm_content=Q1%202022%20Industry%20Insights%20Newsletter

Annex VI to Clinical Trial Regulation 536/2014 Risk assessment-based concept of an interim* solution on expiry date labelling of the immediate packaging of Investigational Medicinal Products (IMPs) (March, 2021) Available At: 

https://www.efpia.eu/media/589700/annex-vi-to-clinical-trial-regulation-536-2014.pdf

EU Clinical Trail Regulation: Annex VI Period of Using Labeling Requirements (March 2017) Available at: 

https://ispe.org/pharmaceutical-engineering/march-april-2017/eu-clinical-trail-regulation-annex-vi-period-using

WWDC: Apple’s NFC plan is a big developer opportunity (May, 2018) Available at: 

https://www.computerworld.com/article/3276649/wwdc-apple-s-nfc-plan-is-a-big-developer-opportunity.html

Accelerating Clinical Trials in the EU (ACT EU) Delivering an EU clinical trials transformation initiative. (January, 2022). Available at: 

https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/accelerating-clinical-trials-eu-act-eu-delivering-eu-clinical-trials-transformation-initiative_en.pdf

Accelerating Clinical Trials in the EU (ACT EU) Delivering an EU clinical trials transformation initiative (January, 2022). Available at: 

Proposals for legislative changes for clinical trials (January, 2022) Available at: 

https://www.gov.uk/government/consultations/consultation-on-proposals-for-legislative-changes-for-clinical-trials/proposals-for-legislative-changes-for-clinical-trials#proposals

European Commission Website – Public Health- Clinical trials - Regulation EU No 536/2014 

https://health.ec.europa.eu/medicinal-products/clinical-trials/clinical-trials-regulation-eu-no-5362014_en

Recent updates from regulatory bodies are providing more confidence in integrating different forms of trials and technology.

Evaluating Global Regulatory Landscape for Driving Digital Innovation in Supply Management

Calyx announced that long-term client, Krka, is expanding its investment in the Calyx Regulatory Information Management (RIM) system for an additional five years.

Read more about Krka's use of Calyx's RIM 

Krka to use upgraded Calyx RIM, now on Microsoft Azure, for an additional five years.

Krka Extends Use of Calyx Regulatory Information Management System

Oversight of drug manufacturing and quality control will continue to utilize off-site reviews of documents and operations, as FDA moves to make permanent these approaches that proved efficient and effective during the COVID-19 pandemic. FDA says this hybrid inspection model will remain a regular means for supplementing on-site inspections and will be further integrated into the agency’s oversight operations as the agency endeavors to restore its field inspection program. That task faces added difficulties as a large number of vacancies in the agency’s field force has expanded the task of replacing and training more inspectors and compliance officials.

The importance of using remote regulatory assessments (RRAs) was highlighted by FDA Commissioner Robert Califf and Associate Commissioner for Regulatory Affairs Judith McMeekin in a recent advisory outlining an “optimized approach” for overseeing manufacturers and supply chains “dispersed around the world.

 RRAs won’t replace site inspections, but these top officials emphasize that they can serve as a practical way to ensure compliance, to verify information submitted to the agency, and to inform key regulatory decisions.

Earlier during the pandemic, FDA officials reported they were utilizing a “wide range of oversight tools” to extend the agency’s regulatory reach where on-site inspections were not feasible. In an advisory posted on March 18, 2021, McMeekin and then Acting Commissioner Janet Woodcock highlighted the value of alternative inspectional tools for verifying the quality and compliance of regulated products where on-site examination was not feasible.

 FDA provided added advice on using this approach in a guidance issued in April 2021 on its use of remote interactive evaluations of drug manufacturing and bioresearch monitoring facilities during the pandemic.

New FDA draft guidance now provides more specifics on how the agency will utilize RRAs and how these audits will coordinate with and supplement site inspections.

 In a question-and-answer advisory on “ConductingRemote Regulatory Assessments,” published July 22, the agency says that RRAs will be useful in seeking to confirm information more quickly and efficiently, particularly when FDA is unable to send in staff due to travel restrictions.

The draft guidance clarifies the scope and format of RRAs, the type of situations where they will be requested, and how these approaches will relate to and complement site inspections. The advisory explains how FDA will request an RRA and will carry out the process and notes that there are consequences for a manufacturer that declines to participate in an RRA, even when not mandated.

The guidance also informs stakeholders where compliance with RRA requests is voluntary or is required by statute, a policy that FDA would like to expand. Currently, the agency has stated authority to require compliance with RRA requests by certain food importers and by manufacturers of all human and animal drugs and biological products. Pending legislation, which FDA backs, would extend that policy to all regulated establishments, including food producers, clinical investigators, and manufacturers of medical devices and tobacco products.

Over the last two years, FDA reports that it has used RRAs in evaluating more than 1,470 domestic and more than 600 foreign operations. These methods have identified unreported adverse events, provided information to support import alerts, evaluated how well companies are correcting issues raised in previous inspections, and assisted in making regulatory decisions on premarket submissions. As with other inspection activities, FDA will continue to utilize a risk-based approach to shape RRA requests, examining the location, inspection history, and complexity of products made at a facility.

https://www.fda.gov/news-events/press-announcements/fda-details-optimized-approach-regulatory-oversight-tools-better-protect-public-health

https://www.fda.gov/news-events/fda-voices/fdas-ongoing-use-inspectional-tools-ensuring-access-safe-quality-food-and-medical-products-during

https://www.fda.gov/media/147582/download

https://www.fda.gov/media/160173/download

Citing strong reporting results, hybrid model to continue supplementing on-site inspections.

FDA Confirms Ongoing Reliance on Remote Inspection Methods 

Patient-centric healthcare data technology provider Seqster PDM, Inc. announced a three-year partnership with Boehringer Ingelheim to use the SeqsterOS to close the Real World Evidence (RWE) gap. To that end, SeqsterOS will provide patients in all of BI's studies access and engagement with longitudinal RWD, with full patient consent and control.

with Seqster CEO & Co-founder Ardy Arianpour.

Patients in all studies can consent to longitudinal data use to accelerate RWE

Boehringer Ingelheim to Use Seqster Platform

Labcorp announced that it will spin-off its Clinical Development business, which will create two independent, publicly-traded companies. Labcorp will comprise its routine and esoteric labs, central and early development research labs, as well as its extensive, advanced global laboratory network. The as-yet-unnamed CRO business will provide Phase I-IV clinical trial management, market access and technology solutions to pharmaceutical and biotechnology organizations.

Over the last four quarters ending June 30, 2022, the Clinical Development business delivered total revenue of $3 billion and grew 8.0% on a CAGR basis from second quarter 2019 to second quarter 2022. The Board of Directors, executive leadership, and company name of the Clinical Development business will be determined and announced in the future as plans for the spin-off continue to progress.

In November 2014, Labcorp announced the acquisition of CRO 

, providing the basis for its greater clinical development capabilities. 

Two independent, publicly-traded companies will result upon completion. 

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