Lisa Henderson

For many years, it’s been discussed that FDA is a barrier to change…mostly related to a change in process or a change of technology. Though regulators would routinely come forward to reassure the industry that their guidance documents supported change, fear and insecurities still abound. It does take time to change, but the FDA really does support advances in clinical trials. But every so often, it is reassuring to hear it in the agency’s own words, especially now with talks of decentralized trials and patient participation. Recently, FDA has been asked about ongoing changes in clinical trials from the point of decentralization and participation.

Last month, Amy Abernethy, MD, PhD, principal deputy commissioner and interim CIO for the FDA, gave the opening keynote for the Veeva Systems R&D and Quality Summit. As a hematologist/oncologist and palliative medicine physician, and internationally recognized clinical data expert and clinical researcher, she shared her compelling views on those discussions. She set the stage by saying the practical reality of clinical trials features two important responsibilities, (1) keep study participants safe and (2) generate a high-quality data set that will answer the question at hand.

For that, Abernethy stressed that the “site is critical to that entire set of activities.” And specifically for decentralized clinical trials, she said: “I think about a series of solutions that help physicians or other healthcare providers involved in the clinical trial process and keep patients safe. It also allows us to be able to have, even if it’s virtual, eyes on the person receiving care to make sure that we know how the patient is doing.”

Abernethy continued, “I think that from the perspective of the site investigator involved in decentralized clinical trials, they still are going to continue to have this incredibly important central function—even if it’s a decentralized clinical trial—of continuing to lead that focus of patient safety, and then also contributing to the clinical trial in alliance with the study protocol.”

At a closed event, a member of FDA declared that “Participating in clinical trials is an imposition on people. If we can move to trial designs that are more pragmatic, with less burden and allows for more participation…” that would be a plus.

There was also the hint that the speed with which FDA issued guidances in the early pandemic could become the norm; the process would shorten to release with a more fluid approach to alterations or changes as needed.

The FDA is moving with the times, and with speed. It will be up to some in the industry to respond in kind.

 is Editor-in-Chief of Applied Clinical Trials. She can be reached at 

Articles

The FDA hints that their increased speed in issuing guidances during the pandemic could become the new norm.

FDA Reassurances Always Go a Long Way

Let’s take a short vocabulary quiz. Full in-person, hybrid, virtual, remote, synchronous, asynchronous are terms used for, a) descriptions of clinical trials, b) types of cars, c) descriptions of learning models for schools during COVID-19. The answer is “c,” but the comparison I was going for is clearly trial design or type of site model. I left out decentralization because that would have been a huge giveaway, and I haven’t seen that term used yet on any school K-college curriculum. While I struggled with understanding synchronous and asynchronous as the two forms of online learning in the beginning, I have it down now. There has been a lot of discussion in clinical trials about the difference between virtual and remote, and I think that has been cleared up also. So let’s dive into the future of hybrid, decentralized, and remote trials.

According to a recent report from Frost & Sullivan, 

“Hybridization of Clinical Trial Designs Reviving Global CRO Market Post-pandemic; 2019-2024,” 

hybrid trials and remote patient monitoring are key trends driving the global CRO market. While COVID-19 may in and of itself be a driving force behind the adoption of both hybrid trials and remote patient monitoring, it is also putting downward pressure on the overall CRO market. The company’s analysis suggested that the current ongoing trial disruptions are effecting revenues for the short-term. Frost & Sullivan further expects that revenue will be back to its original growth trajectory by 2024–2025, with a compound annual growth rate of 8.2% and $63.83 billion revenue by 2024, up from $43.03 billion in 2019.

The report also suggested that adoption of hybrid trials by CROs could increase their growth opportunities by enabling uninterrupted trials and cost savings of 15% to 20%; by focusing on long-term collaborations that offer substantial cost advantages with 8% to 13% savings across different trial phases; by leveraging new technologies, such as risk-based monitoring, eConsent, wearables, and telemedicine patient visits; and implementing direct-to-patient model clinical trial supplies

 has learned in discussions with clinical trials professionals, there is no shortage of innovative ideas being put forth in both the CROs and investigative sites. There are successful transitions coming from organizations including eConsent (how about virtual reality consent and consents that span clinical to research in an institutional setting?); telehealth for patients that did require a bit more convincing for physicians; launching patient recruitment websites in days down from weeks; and a survey that suggests people have the skills for these new clinical trials, they just need support in adapting to the digital world.

While I’m a supporter of remote and hybrid trials to support patients’ needs and expansion of availability of trials to more people, I have questions about the future of the same for long-time learning purposes. For the clinical research enterprise, the pandemic is bringing great innovation more quickly to an industry willing to move forward with purpose.

ACT's Editor-in-Chief, Lisa Henderson, assesses the sustainability of remote trials.

The Future of Remote Trials

As of Sept. 1, 2020, ClinicalTrials.gov lists 284 clinical trials as suspended. Not all of those trials are suspended for COVID-19, some are holdovers on financial issues, R&D problems, etc. And while upwards of 1,200 trials were suspended at the peak, 

, 67% of healthcare experts plan to use decentralized clinical trials in the near future due to COVID-19. To address the walk back to clinical trials, 

 is planning a virtual event mid-November that will highlight the successes that clinical trials experienced during this time, and open dialogue for the continued innovation within the industry.

Solutions to enhance patient participation

According to press releases and reports of the time, solutions to ensure that participants could continue to stay in clinical trials safely were on the rise. In 

, we noted that the “newer methods” of patient-centric clinical trials trend toward home study visits, telemedicine, and remote patient monitoring, have been happening over the past few years, but uptake was slow. We know the numbers for low patient enrollment: Tufts Center for the Study of Drug Development found no significant differences in the mean number of patients enrolled per site or by therapeutic area in 2019 versus 2012. The study also showed that late-development studies had a higher average drop-out rate in 2019 (19.1%) than in 2012 (15.3%).

During the pandemic, service providers offering safe patient access and decentralized model enablement, found increased interest in their business. Darcy Forman, vice president of clinical operations for Science 37, a provider of virtual clinical trials, commented at the time, “We have been unbelievably busy with this pandemic as sponsors are wanting to transition to a virtual model. It’s really accelerating, and they are finally pushing through their hesitancy.” 

 to implement their cardiac safety, respiratory, and imaging solutions to capture data from participants in decentralized trials.

, Michelle Longmire, MD, co-founder and CEO of Medable, reported increased business across the board. She said, “…everyone from existing partners to totally new partners were calling us around the clock looking for help. We created a workstream for rapid validation and qualification of individual studies, as well as partners, so that we could deploy technology quickly. What was never thought possible before was suddenly turned around in a matter of days to a week. We literally turned months-long timelines into days—and this was key, as was the ability to deploy technologies with necessary processes around patient data privacy, security, and data quality.”

That sense of urgency and can-do attitude is what our event will highlight. We are currently recruiting speakers to share their experiences in the following topic areas: the patient participation piece; the New Clinical Trial and how sites and sponsors transitioned to address the barriers of COVID; and Ensuring Data Quality and eSource Implementation—again another “old is new again” strategy to gain forward momentum in the clinical trial discourse. We look forward to sharing your ideas during this forum.

A look into the future based off what we've learned about trials during the pandemic.

Trial Innovation Beyond the COVID-19 Pandemic

 that interruptions of clinical trials due to COVID-19 have been on the decline since June, this 

, also from GlobalData, detailed the reasons behind trial disruption. The primary one, at 67.3%, was suspension of enrollment; delayed initiation of planned trials followed at 18.4%, and slow enrollment at 14.4%. Of the trials affected by the latter, 20.7% were due to the availability of sites and investigators.

The majority of disrupted trials were in Phase II, at 44.8%; Phase I, with 26.1%; Phase III, at 21.7%; and Phase IV, with 7.4%. By therapeutic area, oncology has the highest number of disrupted trials, with 33.3%, followed by CNS, at 16.1%, infectious disease (9.3%), gastrointestinal (9.1%), and respiratory (7.7%).

But, as the data showed, trials are coming back again. And that’s where the cracks in the traditional approach are being exposed. It is why so many articles and observations from experts in clinical trials were calling on the industry to adapt, learn, and change so the fundamental breakdowns in clinical trials can be addressed. You can peruse our online articles and blogs from the past four months for a clearer picture of the calls to action.

 we posted was from Gen Li, PhD, president and founder of clinical development analytical products and services provider Phesi. In this article, Li urges the industry to reexamine its delayed, suspended, or low-enrolling studies on a deeper level. Clearly, sites and investigators were unavailable during the early days of the pandemic in the Northeast and now again in the South. But what other factors existed besides COVID?

Li suggests that many trials are poorly designed from the outset, “so their execution is intrinsically flawed—and would be highly likely to fail or require rescue, even if COVID-19 had never happened.” Specifically, Li says that poorly executed site activation is one of the main drivers of slow patient enrollment. If sponsors now take a data-driven approach, by identifying high-performing sites or finding the most relevant CRO with a performance record in the indication under study, they could potentially avoid a trial destined for failure.

Another area of examination? Competition between studies and sites, which has significant impact on patient enrollment. Li uses the example of the number of recruiting sites in Crohn’s disease that increased in the three years before COVID-19, from under 2,000 to more than 9,000, and without acknowledgment of the limited patient population. This has led to poor country allocation and site selection. It leads to the reality that some of these programs will have to be terminated and reallocated to those with the best chance of succeeding.

Many have taken advantage of the processes and technologies to help overcome the limitations of trials compounded by the pandemic. We look forward to showcasing more success stories around these technologies as well as their acceptance by the global regulatory authorities to ensure trial continuation. But for long-term change, it will take a concerted effort by many to keep trials moving in an upward motion toward excellence.

While clinical trials are starting to make a return from COVID-19-related interruptions, cracks in their traditional operation are being exposed.

Lisa Henderson

Articles

FDA Reassurances Always Go a Long Way

The Future of Remote Trials

Trial Innovation Beyond the COVID-19 Pandemic

COVID Exposes the Cracks in Trial Problems