Christine Bahls

 Industry recognition for the clinical research as a care option, or CRAACO, movement goes to The Conference Forum, which has hosted the conference of the same name, for seven years. This year’s CRAACO event was held Sept. 12 and Applied Clinical Trials, at the time of this writing, is looking forward to attending and learning more from many of the speakers featured in this article.

At the Icahn School of Medicine at Mount Sinai, researchers are laying the groundwork for future massive genotype-based studies. Within three to six years, the database is expected to hold the sequenced DNA samples of one million people—all patients of the Mount Sinai Hospital System.

In Oregon and California, researchers wanted to see if people who were overdue for a colon cancer screening test would take one if they were mailed a FIT test. It took one year to identify 41,193 people in 26 federally qualified health clinics.

And in the Northwell Health System, researchers culled their electronic health record (EHR) system for patients with specific COVID-19 symptoms to help them determine whether the use of famotidine would shorten the number of days a COVID patient contended with symptoms. They found 55 fitting the bill within six weeks.

At the University of California, San Francisco, and across the country at Temple University Hospital, oncologist researcher Laura Esserman, MD, MBA, and pulmonologist Gerard Criner, MD, respectively, have been using their EHR systems for years to run pragmatic trials and to find eligible clinical trial patients in their respective clinics.

 Once found, the medical teams embed the trial into patient care.

If you are wondering if this article concerns EHRs and compatibility, you’d be correct. If you are thinking it concerns ways in which clinical trials can be run with less money and fewer data points, you’d also be accurate. And if you think it’s about improving patient care where they receive care—all while advancing research—you are spot on.

What these researchers are doing bears little resemblance to the classic, rigidly run, interventional clinical trial. Trial phases blend into one another. In some cases, molecules under inspection that aren’t working are eliminated as early as possible from the trial; molecules that do work are tested under more scrutiny. With clinical trials, time means money.

A key point: All enrolled patients were found after serious mining into the provider’s EHR. So yes, point of care works in large healthcare establishments, with fluid EHR systems. So yes again, point of care is not a routine approach in most trials. A serious problem, says Amy Cramer, steering committee board co-chair for the HL7 FHIR Accelerator Vulcan, is that most trials are still conducted using paper processes. Researchers need the data before the trial is started, she adds.

It is all about the technology, Christina Brennan, MD, vice president, clinical research at Northwell Health, tells 

 “We wouldn’t have been able to do [the famotidine trial] without” the EHR system, she says. Everything Northwell could determine about its potential recruitment prospects came from its system, as did all inputted data that led to results. “We screened thousands of patients for eligibility.”

At Temple University Hospital, running trials and treating patients have gone hand in hand for a few years. “Our clinical research program is not separate from our clinical care or our academic mission,” said Criner, also chair and professor, Thoracic Medicine and Surgery, Lewis Katz School of Medicine at Temple University; and director, Temple Lung Center, in a published interview

, who also reviewed this included information for accuracy. “If you embed it into your care program and your care program has to address what the needs of the patient community you treat are, you can’t help but make everything better—your research, clinical care, and training.”

As to what this clinical trial approach is called, there is no universal name. Brennan says she didn’t think point of care was applicable, and preferred clinical research as a care option, or precision/personalized medicine.

According to FDA—which, by the way, is a big supporter of embedding clinical research at the point of care–“Point of care trials take place in a clinical practice environment and make use of clinical infrastructure and personnel for trial-related activities.” A successful trial, an agency spokesperson continued, “may shorten the time needed to obtain safety and efficacy data for medical products.”

But do not think these trials are allowed to confuse real-world data (RWD) with real-world evidence (RWE). FDA, in its 2018 framework document,

 defined RWD as the data relating to patient health status and/or the delivery of health care routinely collected from a variety of sources, and RWE is the clinical evidence regarding a medical product’s use and potential benefits or risks derived from analysis of RWD.

Says researcher Rachele Hendricks-Sturrup, DHSc, research director for real-world evidence at the Margolis Health Center at Duke University: “Healthcare data is not real-world evidence until it is combined with real-world data.”

Taking the 30,000-foot view, Jodyn Platt, PhD, MPH, an assistant professor of learning health sciences at the University of Michigan, says health care should be viewed as a point of learning. “There’s a fine line between quality improvement and research” in order to learn from that data to give better care.

But it could be worth it, Platt says. If researchers have the opportunity to use a system that allows them to see what is done correctly or not, “we have the potential for making the [healthcare system] better for everyone,” she says. “If we can think strategically, we can make the process better.”

Esserman, who built her approach to breast cancer trials in the early 2010s, described how the process works at the UCSF Breast Cancer Center. All registration data are collected and cleaned within 24 hours.

Each patient’s information regarding response to the therapy is used to build on to the next patient. This is all about finding early indicators of response and eliminating data detritus, which, says Esserman, clouds results.

The idea, she adds, is to have real-time data collection. “All data sets must be complete before randomization,” Platt says. “We are trying to focus on the data that inform the primary endpoints, so that we are less burdened with data of ancillary interest.”

She elaborates that most data, 90%, collected in trials is irrelevant because it is never used or “not germane to the primary endpoint.” And since all data collection requires time and money, more thoughtful decisions about what to collect matters.

It is a model other are adopting or participating in, including FDA and the National Cancer Institute.

In Northwell’s double-blind, placebo-controlled study on famotidine, researchers collected 1,358 data points from 55 patients with COVID; one arm got the famotidine, the other, placebo. Those in the control arm improved three days more quickly. All samples and all treatment were administered in the patients’ homes. The cost of the trial was less than $1.5 million.

 The success of the study and its cheaper cost have convinced Northwell that the model is worth incorporating into their trial formats. Along with this more patient-centric approach, Brennan says that hybrid trials are being requested more by sponsors.

Between 2014 through 2016, Mount Sinai used EHRs to find 2,050 patients of West-African ancestry with hypertension, no chronic kidney disease, and genotyped them for the 

 risk variant, which could be deadly for those subgroups.

 Once patients were found through the EHRs, study coordinators mailed invitations and then followed up with phone calls of those who declined, “and intercepted potentially eligible patients at clinics when they were hard to reach,” according to the study. The point of the trial was to quickly return genetic results to a randomized group to see how patient outcomes would be affected.

The intervention group reduced their blood pressure and adopted more healthy behaviors. The high-risk patients dropped their systolic blood pressure by 3.6%; the controls dropped by 1.3%.

“These results may support an approach of broad implementation of genetic medicine in primary care for certain use cases,” concluded Girish N. Nadkarni, MD, MPH, Irene and Dr. Arthur M. Fishberg professor of Medicine, Icahn School of Medicine at Mount Sinai, et al., in the study.

As to the question of just how common point of care trial research actually is, everyone interviewed had the same answer—it isn’t.

“There is a lot of activity in this space. But it is fragmented, as is our healthcare system,” says Platt. Her specialty is studying trust in the US healthcare system. Developing measures of trust to monitor how trial enrollees are faring is in the works, she she adds. “It is a huge issue because of digital care in the home.” What happens to the data if third parties are involved, or if a startup company that was monitoring patient progress dissolves? “How does your data live with this?” asks Platt.

She and her staff are starting research in artificial intelligence and how patients trust the technology in their healthcare systems. “That is a key research question—it’s a new form of technology that has little oversight, from institutions and government. We need to understand what the public feels like when they have a stake in the field.”

In May, the Duke University Margolis Center for Health Policy published a white paper on point of care-incorporated trials.

 It defined one aspect of the point-of-care scenario as: Using an EHR for enrollment, data collection, and randomization; running the trial where patient care occurs; and combining research and clinical care delivery workflows. “The focus is on the trial participants,” says Hendricks-Sturrup, a co-author. “We want to achieve better screening, consent, randomization, and data collection, then incorporating those finds into routine care.”

The difference between other trial designs and those that use point of care, says Hendricks-Sturrup, is that point of care is designed “to know if the therapy is efficacious across all populations.”

Margolis is working to resolve issues that could impede point-of-care progress, such as who runs the trial, who should pay for it, and how can data be collected and handled in an easy fashion across different systems? A major point is not adding burden to providers. “We are working to tackle policy,” says Trevan Locke, PhD, assistant research director for Margolis.

As for the blip, researchers for the colon cancer screening trial learned that buy-in from staff involved in the trial is essential. Staff at the various federally qualified health clinics didn’t all do as the researchers asked, like installing a piece of software into their EHRs to find and track possible participants. Researchers stated: “For most of the participating health centers, [this trial] represented the first time EHR tools were used to deliver cancer screening services outside the clinic. Implementation might have increased
with experience.”

Alexander Charney, MD, PhD, associate professor, departments of psychiatry and genetics and genomic sciences, and co-director of the Mount Sinai Million Health Discoveries Program, says that as it acquires patient samples, it is gaining approvals for future trials. No studies are established yet, he says.

“But let’s fast-forward five years,” Charney continues. A sponsor wants to run a trial comparing therapy X to therapy Y, when half of the patients have a certain genetic variant. “If a researcher wants to do that trial, five years from now, patients will already have consented,” he adds. “We have laid the groundwork.”

All 17 hospitals and clinics in the Mount Sinai Health System will be recruiting for this project, which is being underwritten by Regeneron. The volume of patients and unification of Mount Sinai’s operations make the enrollment goal possible, says Charney. His fellow co-director, Nadkarni, says enrollment is going slowly for a purpose.

“We want to make sure systems are good to go,” he tells 

 and that safeguards are working, like ensuring patients are not duplicated in the system. The platform, he notes, meets all NIH and Department of Defense security standards.

Partnering with Regeneron, says Charney, was key to getting the project off the ground. “There is no other way to sequence the genome of one million people,” he adds. Regeneron, notes Nadkarni, will sequence the DNA samples, and then return the patient data.

At Northwell, Brennan said that as each trial request comes in, the team is looking at whether an embedded study can work. Of the 2,000 trials in motion, 5% to 8% are designed as a hybrid approach. Despite all the talk about embedded, i.e., point of care, few are being run that way.

But, she adds, “We don’t want to go back to the former ways and traditional methods of running a trial. When we saw how to pivot in COVID, we were able to [be flexible].”

 is a freelance writer for medical, clinical trials, and pharma information.

Coronado GD, Petrik AF, Vollmer WM, et al. Effectiveness of a Mailed Colorectal Cancer Screening Outreach Program in Community Health Clinics: The STOP CRC Cluster Randomized Clinical Trial. 

Brennan CM, Nadella S, Zhao X, et al. Oral famotidine versus placebo in non-hospitalized patients with COVID-19: a randomized, double-blind, data-intense, phase II clinical trial. 

. May 2022;71(5):879-888. doi: 10.1136/gutjnl-2022-326952. Epub 2022 Feb 10. PMID: 35144974; PMCID: PMC8844971.

https://theconferenceforum.org/wp-content/uploads//2020/09/CRAACO_Q3-1.pdf

Interview with Laura Esserman. The I-SPY Approach to Drug Development. 

Clinical Advances in Hematology & Oncology

https://www.fda.gov/media/120060/download

Nadkarni GN, Fei K, Ramos MA, et al. Effects of Testing and Disclosing Ancestry-Specific Genetic Risk for Kidney Failure on Patients and Health Care Professionals: A Randomized Clinical Trial. 

https://www.quantumleaphealth.org/about-us/board-of-directors

Point-of-Care Clinical Trials: Integrating Research and Care Delivery. Duke Margolis Center for Health Policy. May 11, 2022. 

https://healthpolicy.duke.edu/publications/point-care-clinical-trials-integrating-research-and-care-delivery

Articles

Experts discuss solving the EHR-compatibility puzzle in point-of-care trials.

‘Record’ Gains in Bringing Research Closer to the Patient

means examining a specimen where it is naturally found, or where an event has occurred. These days, in situ could also define the preferred spot for a clinical trial.

Whether it was recognition, for a very long time pre-pandemic, that industry needed new ways to recruit and retain patients, or the success realized last year during the global SARS-CoV-2 vaccine trials, when pharma said we have no choice but to adopt 

–or both reasons–the clinical trial industry is doing a 180, site-selection speaking.

 is in; it guarantees real world evidence because in situ naturally leads to where patients live, are treated, and immortalized, to whatever extent, via their health system’s EHR and other data sources.

What’s remarkable here is how varied are the business models that have evolved to find sites and patients. The sources are extensive–pharmacies, patients’ homes, community hospitals, physicians’ offices. Further, the attempt to include people who are not white, male or of comfortable means, seems real.

What is not varied, said those interviewed, is the goal–consistently but speedily finding and enrolling the right patients, and retaining them in the trial. However, discovering whether the clinical trial services industry is successful with these strategies so far has yet to show up in a peer-reviewed study. Anecdotally, it appears so.

Labeling the clinical trials support industry as ‘niche’ works. Most rely on other niche businesses to help fill a software or service gap if it lacks what a client wants. Elligo Health Research, an IRO, and Syneos Health, a CRO, have a four-year collaboration. Syneos has the clinical trial networks; Elligo has access to Cerner and other EHR systems, said Maria Fotiu, executive vice president, decentralized solutions, Syneos Health.

Healthcare, said Keith Fern, vice president, corporate development, Elligo, has become a heterogenous business. “Partnering with different companies with access to patients in a variety of healthcare settings is very important to [the Elligo] model.” The sophisticated protocols, the move toward personalized medicine, have made eligible patients harder to find, he said via e-mail. Its patient network, he said, surpasses the 100-million mark.

The pandemic’s effect on ongoing and new studies was unprecedented, said Suzanne Caruso, SVP, clinical solutions, insights and analytics, WCG, in a statement. “It led to an environment unlike any we have seen previously. With the increased competition for patients due to the number of new trials, and the struggle hospitals are having finding the staff and time to run trials, the speed of recruitment has slowed significantly.”

In February, Circuit Clinical and LabCorp announced its collaboration. LabCorp, which is also an investor, said Irfan Khan, Circuit’s CEO and founder, allows Circuit to access LabCorp’s network of healthcare systems and centers.

Almost every company interviewed for this story has received private equity support. Trial-support investment, said a consultant, is a safer bet because no risk is involved.

Other trial-support businesses, like Curebase and Reify Health, have designed cloud-based platforms with the primary intent to speed up the site selection, patient enrollment processes, and if the client desires, help with certain elements of the trial itself, like specimen collection. They are neither CRO nor IRO–Reify’s co-founder Ralph Passarella said Reify isn’t interested in labels, but clearly the company is in the trial-support business with its StudyTeam patient recruitment and enrollment technology platform, and its Care Access decentralized research organization that brings clinical trial infrastructure directly to patients, healthcare providers, and communities.

The speculation as to why this find-your-niche trend developed is multi-pronged.

Craig Lipset, founder, Clinical Innovation Partners, told a story in response to the why question.

He was attending the 2020 Summit for Clinical Ops Executives—pre-COVID—when he saw a friend in a hallway. The friend worked at a top five pharma. What’s going on?, Lipset asked. Well, says the friend, we are pulling back from the CROs; we have assembled 100 trial site pros and data analysts. A few minutes later, Lipset met another friend, who worked at another top five company. He asked the same question and received the same answer.

“Before COVID, most [large pharma] had already pulled back site selection in-house,” Lipset said, including those involved in the COVID-19 vaccine trials. It was not a question of saving money, at least immediately, but the need to show that yes, we can find the right sites and assess our own data.

Will more pharma follow? “They tend to move in packs,” he said. “A good idea tends to move quickly.”

Two questions to ponder: Is this new model sustainable? Or will this model, borne out of pandemic-response necessity, revert due to atrophy? Without a concerted, dedicated commitment, to maintain flexibility in trial site selection and enrollment, Lipset said, atrophy will prevail.

As to the other plausible reasons this find-your-niche industry developed:

In the mid-2010s, various studies found that more than half of new investigators would not partake again.

 But the need for more sites, as more trials were going global, was approaching the critical point.

 The amount of time to run a trial, soup to nuts, was getting longer.

It’s hard to speak to an overall trend, said Passarella, noting that the integrated research industry came to be between 2015 and 2019. While CROs and sponsors partnered for decades for the patient identification and recruitment processes, Passarella said people began to realize that to improve study outcomes they had “to really innovate at the site level.”

The trend of the “last half decade is kind of a push in that direction,” he said.

Lipset also had another suggestion. Asking physicians to become investigators is a tall order, just consider the dropout rate of first-time investigators. Without the proper structure, running a trial while running a practice wasn’t worth the physician’s investment, from every point of view. But to have trained trial professionals drop into a “setting and support doctors as investigators,” that provides that needed structure.

And that is where IROs came into being, Lipset said. IROs offer healthcare sites something more sustainable and scalable. Khan calls it the ecosystem of running a trial—from administrative help to training staff on technology to offering data assessment.

Curebase designed software to make trial participation easier for the patient. “Instead of driving to one site to collect vitals, they can see a PCP in town, they can get a blood draw with a mobile phlebotomist at home, an x-ray at a local imaging center, and complete patient surveys on their phone,” said Tom Lemberg, founder and CEO of Curebase via correspondence. Patients have even gotten swabbed in pop-up drive-through centers.

The tech involved includes mobile provider calendars and workflows, along with the healthcare’s own EHR system. According to the Curebase website, its technology propelled the start of a COVID trial in two weeks. It used drive-through testing centers, where patients gave consent and provided samples. The sponsor used its own technology to do the testing.

Jennifer Byrne, CEO of Javara, said its goal is to run trials as a clinical care option. Say a patient learns she has diabetes, Byrne gave as an example. “Her doctor says, ‘here is your treatment regimen. But, if you are interested, we can offer you more. Our healthcare system is running a trial on diabetes that could help you. You can learn more about your disease.’” The patient now becomes a healthcare consumer, and clinical trials become an option with more patient touch points for the patient and trial staff.

“WCG works with all types of investigational sites, including academic centers, integrated health systems, large site networks and independent sites, as well as part-time investigators,” said Jill Johnston, president, WCG Clinical, study planning and site optimization, in a statement. WCG has agreements with over 3,300 institutions, in addition to more than 5,000 biopharma and CRO clients.

With these extensive connections, Caruso observes there’s no one-size-fits-all approach for clinical trial recruitment. “It’s not only that the diseases are so different, so too are the specific patient segments.” She noted that these include people with physical limitations or those struggling with day-to-day issues. If the needs of these patient segments aren’t recognized early and addressed at each site, meeting recruitment goals may not happen.

Very often, said Passarella, recruitment will be hospital dependent. A heat map of a particular disease presence might indicate a heavy concentration in a large city, but it also might pick up a smaller hospital or center that is three hours away that is a better fit for the study. “It matters which hospital or clinic you are talking to.”

Elligo’s Fern described the process for finding patients for a possible migraine trial. The Elligo investigators “searched across disparate data sources, normalizing them for a clinical protocol.” The result: patient level data “that will allow the sponsor to identify highly likely participants for their trial.”

Circuit Clinical, which has a presence in 34 states, approaches mid-size, research-naïve healthcare centers, said Khan. These include the federally qualified health centers, which have large minority patient populations, Khan said. “It is our job to pull as much friction out of the process” as possible for healthcare administrators and physicians.

When it comes to training support, the Circuit ecosystem includes training the investigator’s staff on those technologies that Circuit will use to run the trial.

Oftentimes, said those interviewed, smaller providers do not have the up-to-date tech training needed to run a trial. Staff training is on the menu if staff wants it. “It depends on their appetite for engaging,” said Passarella.

Curebase offers virtual support, especially for research-naïve clinics. Principal investigators get help to oversee the study, while virtual research coordinators help the patients with e-consent, scheduling visits, and so on. The software also automates other processes like payments and data entry, Lemberg said.

 in their own homes; vans take trial personnel to patients’ homes for sample taking, collection, medical checks, and so on. Reify works with research-naïve institutions as well, these healthcare providers might not have the up-to-date software, so staff needs to learn how to use them. “When we go to certain settings that don’t have cutting edge technology, part of what we do is bring it in and make it accessible to staff.”

Byrne addressed another important point. Even though the investigators can unload administrative and clerical tasks, the physician still is responsible for the medical and clinical decisions regarding the patient.

Since 2018, said Byrne, the company has built partnerships with major healthcare organizations, like Atrium Wake Forest Baptist Health, allowing the company a patient base of more than 6 million. Collaboration, she said, is key from a healthcare standpoint.

Khan said Circuit’s diversity numbers are two times higher than the average seen in clinical trials, according to figures gathered between May 2019 through May 2021. “This is not because we targeted certain ethnicities—it is because we operate within healthcare and, therefore, see the populations that represent all of the US.”

Circuit also offers its clients a real-time method to improve if and where it needs to. The Trial Journey platform lets patients go online, discuss their experiences, and rank their treatments and physician encounters, from a scale of 1 to 5. The platform is also open to doctors and the healthcare system itself.

At first, he said, the physicians and healthcare systems were “worried that [patients] will trash them. On Trial Journey, the average rank is 4.2. How do the physicians or health systems react when they see less than a 5? They work to improve it, Khan said.

Many of the IROs use existing health system EMRs, to find patients, but, to be kind, the process is incomplete.

“EMR is the best tool we have, but only 50% of it is useful,” said Khan. “It doesn’t have data that helps determine if a patient is right for a trial. People need to understand how limiting it is.”

There are different approaches to how existing EMR data are used. Elligo, for example, extracts the data needed, then transforms it to become standardized. “We build it as we go,” said Fern.

Byrne said Javara hasn’t come up with a universal language; her team works with the client to standardize its EHR language. “We can pinpoint and ID patients through large data sets.” Which Javara did in a COVID vaccine trial. Of the 100-plus sites, Javara performed in the top 5%. While artificial intelligence can help enhance protocol matching tools, pinpointing the right patient takes a human touch. “It is still not widely appreciated that tech is an enabler.” These tech tools are just that: they supplement the human experience.

Taking into account the in situ trial support options and the IRO/DRO models, is there evidence that the industry is showing demonstrable, trial performance results?

When asked that question, Lipset looked down at his desk, made some rustling noises, and then held up a piece of paper to the Zoom screen: He had drawn a large circle with a line through it. A line of anecdotes, he said, is not evidence. “I haven’t seen this taken on by anybody.

Corneli A, Pierre C, Hinkley T, et al. One and done: Reasons principal investigators conduct only one FDA-regulated drug trial. Cornell Contemporary Clinical Trials Communications. 2017; 6:pp 31

Craig Morgan. 10 Tips for Selecting High Performing Clinical Sites. Oracle Health Sciences. Health Sciences, Study Startup . September 3, 2019.

New support models range from flexible software platforms, IROs, and DROs.

The Evolution of Site Selection

First, what is crystal clear: the spate of mergers, acquisitions, and partnerships involving CROs is ongoing and evolving.

Second, what’s still blurry: how these business transactions will impact the future of the CRO industry, for better or worse. It’s not a couple of factors that propel these pacts. There are many—some permanent, some temporary, with others unknown. And still more have the indelible stamp of
“COVID-caused.”

None is inconsequential: advancing digital technology, globalization of clinical trials, changes in clinical trial design, the inflow of private equity dollars, fewer sponsors lost to mergers and acquisitions, more CROs, the costs of clinical trials, precision medicine, lack of available talent, and—an under the radar trend—the continuing challenges of chronic disease. More people are developing them, but true cures elude pharma. One report says chronic diseases are likely to “support the growth of the global clinical trials market to a significant extent.”

The industry felt the impact of the pandemic, not all of it bad. It forced suspension of trial activity or its abandonment, thereby slashing income, but it also revealed ways to grow, either through an M&A, or how to morph from a jack-of-all-trades to a niche-specific entity.

“The trend toward more patient-friendly trial options is here to stay,” said Peter Benton, CEO, Worldwide Clinical Trials. “The industry is finally acknowledging the need for a toolkit of decentralized research methods and flexibility built around the patient. CROs have a tremendous opportunity to continue guiding sponsors toward solutions that meet them and their patients wherever they are.”

The pandemic also showed industry that it could reduce risk by shifting the weight. Processes that allow remote audits and monitoring, previously considered too risky, are now risk mitigators. “We adopted them, we experienced success with them, and now the ‘risk’ aspect is gone,” Benton said. That risk-sharing is driving continued technological evolution.

COVID forced everybody onto the risk curve, said Christine Dingivan, CEO of global full service CRO, Emmes. “Digital development and technology are just exploding.”

Two interesting maybe-trends: Many people interviewed for this article said that some pharma members, perhaps looking for more control over the management of their trials, let alone cost, are taking CRO functions in-house. One reason they can do this is through a bevy of new vendors, who are devising digital solutions and services to address the chronic migraines of the clinical world: enrollment and site management.

These vendors also have a lot of money from private equity. “It’s incredible,” said Henry McNamara, senior vice president, general manager, Oracle Health Sciences.

Some examples of the private equity cash flow includes Goldman Sachs’ investment of $230 million in 4G Clinical, a developer of randomization and trial supplement management software, two months ago. In May, the investment arms of these household names—Bayer, Hitachi, Samsung, Sony, Unilever—raised more than $200 million for Huma Therapeutics, whose DCT software lets patients trial-in-place; home, hospital, nursing home.

Another tech company that has caught private equity attention is Reify, whose valuation hit the $2.2 billion mark after a recent C round added to the coffers. Reify has two software products—StudyTeam and CareAccess—the former for patient recruitment, the latter for running decentralized trials. The true north of Reify, said co-founder Ralph Passarella, is to predictably enroll trials in three to four months, beating the average time of 1.5 years.

Mike Jagielski, CEO of KCR, an international clinical development solutions provider, said underestimating what these new technologies can do, from a business perspective, is unwise. These products, he said, create incredible organic growth opportunities for companies like his that can scale in a controlled way to “capitalize quickly and efficiently on new platforms, like Veeva.”

Similarly, said McNamara, CROs want Oracle to design agile systems that can respond quickly to change and adopt new service models, per pharma’s new direction.

From a 30,000-foot perch, M&As are a large example of an industry revamping itself. The larger mergers and acquisitions, said Jagielski, have established engaging in M&A as “part of doing business.” A 2020 report called them a “primary factor” in the growth of global CRO services market.

Casey McTigue, an executive director at SRS Acquiom, an M&A services firm, put it this way: “We have seen record setting volumes for M&A.”

In 2019, the life sciences recruiter ProClinical considered the following CROs worthy of close attention from investors and pharma alike: PPD, Medpace, PRA Health Sciences, KCR, ICON, IQVIA, PSI, Parexel.

Of the eight, three still stand alone; the rest have merged or been acquired. Obviously, investors and pharma already were paying attention. ThermoFisher acquired PPD earlier this year; ICON plc now owns PRA Health Services; Parexel is now owned by Goldman Sachs and EQT—the smaller of the group, PSI, Medpace, and KCR, stand alone.

The pandemic crystallized these truths: decentralized trial design has value and the CRO industry is not immutable to financial sledgehammer.

One study, which examined more than 62,000 trials started before and during the pandemic, found that the number of US-initiated studies between February and May 2020 was 57% of what would have been expected had the pandemic not occurred.

A GlobalData survey released in July 2020 found that 322 companies announced their trials had been disrupted; most were in Phase II.

 More than 67% of these trials stopped because enrollment was suspended.

That’s a large monetary hit for the CROs, considering that 72% of all trial sponsors employ some CRO talent, according to a 2015 Research and
Markets report.

For CROs, trials ground to a halt, said McTigue. In turn, trial cessation “impacted our deals with [sponsors] quite a bit. I will say there were a substantial number of disputes” over missed milestones.

Even before the latest M&A moves and the pandemic, CRO specialization was a way CROs could differentiate themselves in an industry dominated by large companies. For the smaller CROs, specialization is a matter of survival. Based in Rockville, Md., Emmes, said Dingivan, has been a “long-standing partner” of the NIH and National Institute of Allergies and Infectious Disease. The company specializes in biostatistics and infectious disease and 20% to 25% of its staff worked on COVID-related studies in 2020. Last year, the company created Emmes Biotech to expand its work with federally-backed trials.

McNamara said specialization “has accelerated because of the science.” Biomolecules, biosystems, combination therapies, orphan drugs, rare diseases…all require deep knowledge, he said, not only for managing therapeutic trials, but also their different phases. CRO regulatory experts are also valuable, he said, such as those working with academic centers or with the federal government.

Another reason to merge or acquire is to literally cover more ground.

That was a good reason for dMed Global, based in Shanghai, and Clinipace, with headquarters in N.C., when the two merged in April. Alira Health, an advisory firm based near Boston, acquired CROS NT, a CRO based in Italy. Dingivan said that when she was looking for a firm for Emmes to acquire, she chose a CRO based in Prague called Neox because of its network throughout Eastern Europe. Another CRO acquisition, Orphan Reach, has allowed Emmes to become well-versed in the rare disease space. Behr-man Capital funded both acquisitions.

The Asia-Pacific area has become attractive to sponsors because it’s cheaper to run costs there and because of its assets, namely larger populations of people, patients and physicians.

Then there are those CROs that wish to complement existing service offerings.

Alimentiv Health Trust, parent of the GI-focused CRO Alimentiv, acquired the CRO McDougall Scientific in March, and a month later launched AcelaBio, a histopathology and precision medicine research lab for global clinical trials.

Think Research, in a venture-backed move, acquired the CRO BioPharma. Think Research, based in Toronto, provides technology products to healthcare facilities, including those that serve seniors. Combined, their network covers 2,800 hospitals, clinics and long-term care facilities, and 200 research and pharmaceutical companies, a press release says.

Since the combined R&D outlay of the top pharma houses now hovers at the $100 billion—and that majority of trials have CRO involvement—even the math challenged can appreciate the CRO industry’s losses, or gains, depending on the road chosen.

But the CRO industry has already proved
its resiliency.

Despite changes in market conditions between 2008 and 2019, SRS Acquiom found that of the 227 private life sciences deals in which it was the shareholder representative, 163 had earnouts, the potential dollar figure more than $37 billion. In its 2019 Life Sciences Deal Terms Study, SRS Acquiom estimated that milestones due by mid-2019 have been achieved on average 33% of the time in biopharma (paying 33% of earnout potential dollars).

Some trial sponsors, said those interviewed, are changing their relationships with CROs by bringing CRO services in-house. One source in pharma said the move in-house is predicated on the success of DCTs and eSource. But the switch isn’t a topic of conversation among her peers, which “raises the perception this is what is happening.”

Said Passarella: ”Our industry is in an interesting state of flux, we are seeing internal shift. Sponsors are getting better support to run studies, but it’s too early to see how everything will shake out.”

Craig Steger, senior vice president, Life Sciences Outcome Capital, LLC, said Outcome did not uncover that trend in a recent report. “The only transaction that we know of where pharma or biotech acquired a CRO, whether in the clinical or pre-clinical space, was when UCB pharma acquired Beryllium Discovery [in 2017].

“I suspect that this may be a talent play,” he wrote in an email.

McNamara concurred...the need for talent is another reason for consolidation. He added that much industry talent is nearing retirement, as well as turnover. Employee turnover in the CRO industry doesn’t seem to be slowing down; before the pandemic, turnover was 24%; in November 2020, it was 21%.

On LinkedIn, CROs are offering sign-on bonuses to fill the roles they need. Charles River offered animal care associates $1,000 to come aboard, while formulation technicians would receive $750. Despite the duplicate ads and the occasional non-CRO job ad, LinkedIn, in early August, showed 40 pages of ads, each with 25 job offerings, for roles that CROs needed to fill. Many of those ads had fewer than six applicants.

Dingivan said she didn’t think the CRO industry was in imminent danger of folding in on itself, due to the new technology firms, mainly because this country’s EMR systems have yet to connect. Trial sponsors need standardization for global-wide trials. The other thing, she said, is that these firms, like Google’s Verily, need a regulated infrastructure to run trials. “You can’t just know how to build a plane, you need the regs, too.”

M&A is always a distraction, as compared to organic development, said KCR’s Jagielski. The extent of the disruption depends on whether it’s your CRO that is acquiring or was acquired. “If it’s the former, it’s less destructive,” said McNamara.

But always count on a talent exodus. “The number one objective is to preserve talent,” said McNamara.

When two companies come together, said Jagielski, the hard part is figuring out what to do with the combined labor force. “In our business you are not buying IP, you are always mostly buying people,” said Jagielski, who has no intention of merging KCR with anyone, unless KCR stops enjoying “double digit growth” year after year.

Said Benton: A merger can force sponsors to reevaluate their relationship with the new CRO, or perhaps look for a new one. If that happens, the integration can lead to turnover, to system-integration irritations and service disruptions. “Integration can take years.”

Businesswire. The Worldwide Clinical Trial Industry is Expected to Reach a Value of $57+ Billion by 2026 - 

Fortune Business Insights. How Contract Research Organization Services Market Will Dominate In Coming Years? Nov. 25, 2020.

https://www.proclinical.com/blogs/2019-5/top-10-contract-research-organisations-cros-to-watch-in-2019

Unger JM, Xiao H. The COVID-19 pandemic and new clinical trial activations. 

GlobalData. 67.3% of clinical trials disrupted by COVID-19 are due to enrollment suspension. July 1, 2020.

Ben Adams. The top 10 pharma R&D budgets in 2020. Fierce Biotech. April 6, 2021.

Andy Studna. Turnover for Clinical Monitoring Remains High. Applied Clinical Trials-04-01-2021, Volume 30, Issue 4

Technology, talent and specialization add up to a plethora of industry M&As.

The Post-Pandemic CRO Landscape

Our apologies to those who still wince when reminded of the following figures.

But because these data illustrate successes, or lack thereof, of clinical trials from the past, they serve as an outcomes baseline for the future: Will future outcomes be based on the types of protocols used in the COVID-19 vaccine trials, or will results be a carbon copy of pre-2020 study figures?

Between 1998 and 2015, Hwang et al. found that of 640 novel therapies, 54%, or 344 therapies, failed in development; the FDA approved 36%, or 230. Most failed because they didn’t reach their endpoints, while 17% were pulled for safety reasons. The remainder were abandoned for unexplained commercial issues. The common denominators among the approved therapies: orphan designations and mega-sized company sponsors. Only 10% were approved in other countries.

Postapproval figures are also worthy of note: Of 222 novel therapies approved between 2001 and 2010, 123 of them were named as the cause of a postmarket safety event; three were eliminated from the market, 61 received boxed warnings, and the rest were the subject of an FDA safety communication.

Techniques that were demonstrated in COVID trials, many of which are decades old, could help stop the wincing. By using different trial designs, such as master protocols; using biomarkers on a regular basis to ensure accurate populations; adopting a new mindset about the purposes behind Phase I and Phase II trials; and giving investigators the time and tools to learn new skills—a shift could happen, said those interviewed.

For example, the Recovery trial, the University of Oxford’s mammoth intent-to-treat COVID-19 study, has various stakeholders, including the Gates Foundation and the Wellcome Trust. Designed for flexibility so investigators can make real-time decisions once an arm produces data, be it thumbs up or down, the protocol puts no restrictions on enrollee numbers or their ages. When dexamethasone proved helpful, it became a standard of care. When the opposite proved true of hydroxychloroquine, that trial arm was dropped. “There was a rolling review,” said Brigid Flanagan, founder of Oriel Research Services, Ltd. “There is no reason it can’t be done going forward.”

Different stakeholders have different definitions of success, said Bill Barry, PhD, senior statistical research scientist, Rho Inc. They will all approach the trial design differently—intent to treat? Delineate which subset will see the best treatment results? To make an umbrella or basket trial work, they need one strategy to rule them all. “Reaching consensus is the challenge.”

So while the technology is willing, the human buy-in could be termed weak. Humans tend to act unscientifically on occasion—like extending a trial whose drug has no future because of heavy emotional investment. That is not evidence-based decision making, said Mike Rea, founder and CEO of Protodigm, which advocates using early trial phases for exploring what the molecule or therapy can be used for, and in what diseases, including subsets. “If you’re just collecting information to say yes,” the trial will ultimately fail, he said. “It happens a lot.”

Trials todsy are more tailored than necessary, said Ken Getz, MBA, founder and board chair, CISCRP and director and professor, Tufts Center for the Study of Drug Development, Tufts University School of Medicine. “We see trials so highly customized, introducing approaches that are unique. [But] when you try and measure at the macro level, you see variation.”

Shorter trial times. Improved patient safety. Less bias, fewer ethical concerns. More risk modification. Especially if biomarkers are involved.

In traditionally run trials, specimens go to a lab and investigators wait for the results. Today, adaptive design allows investigators to add, drop or expand arms, depending on the data, all in real time. All these, said Barry, speed up the trial’s progress. “Biomarkers give incredible new information. Once you incorporate a biomarker into a study, there is less risk of bias.” Adaptive is also considered more ethical by some because patients have better odds of getting effective treatment, quickening pace of treatment discovery.

And it speeds up finding safety issues. “In general, by being able to make changes while the study is underway, patients with safety issues can be discontinued in that cohort, or moved to another group, so it exposes them to less risk because it’s all done in real time. And because the adaptation strategies were approved before the trial started, there is no waiting for additional regulatory approvals,” said Getz.

The Stampede trial, which is evaluating eight treatments over 15 years for locally advanced or metastatic prostate cancer, would—in separate two-arm trials—have taken more than 40 years to complete, according to investigators at the University of Oxford. Progression between phases is reportedly glass-smooth. It started with six arms, but has since dropped two, and added a further three. Wrote one researcher, had these therapies been tested traditionally, we “would simply never [have been] cost-effective for funding outside the program.”

Serial assessments can expand hypothesis, from just does it work for patient Y, to a more complex understanding. You can ask more complex questions, Rea said.

Early phase trials, said Rea, should be exploratory; learn what the drug or molecule can do, do not try to force data. The real risk, he said, is in missing opportunity because the molecule or drug wasn’t asked the right questions. Success involves preparation—determining which molecular or therapeutic pathways seem viable, and then making decisions as the data come in. “Our biggest observation is that there is not enough observation in Phase I.”

But some hesitate on costs. Said Rea: Adaptive trials shouldn’t cost more money “if you do the characterization early, it actually saves money because you’re not doing the failed phase.” A well-designed plan should also lead to easier recruitment.

Traditional trials that become overburdened with complexity, are more customized, which also lengthens the process. Said Getz, “[Customization] is the enemy of speed and efficiency.” Getz says the longer adaptive trials stay out of the mainstream, database lock cycles will continue expanding. Trials now have at least three data sources, adding an average of five days to their database lock. Getz has written the number of days will increase without infrastructure improvements, at the least.

An advantage of biomarkers is that the baseline biomarker could be predictive, said Barry. “A blood draw can measure how enrollees are reacting to the drug. Blood draws are cheaper, and the readout can happen quickly, and consequently, so can decisions to change strategies. That is a key element.”

Assays can be expensive, but they continue to go down in price, Barry said. The potential gains are more efficient, smaller trials. “Doing an enrichment study on only biomarker-positive people can be much cheaper than testing in a full population,” Barry said.

There is another issue with consistent biomarker use, said Flanagan. Patient accessibility. Most patients do not go to academic health centers. If they have no transportation, they will go to a local physician who likely won’t explore a biomarker-based treatment. “I think people are pressed for time. In academic centers, researchers have assistants who can look at biomarkers.”

That is, if they can be gathered relatively easily. The known Alzheimer biomarkers, Aβ1-₄₂, T-tau, and P-tau

 appear in cerebrospinal fluid, not an easy or painless draw. And PET scans, said Laurie Ryan, PhD, chief of the Clinical Interventions and Diagnostics Branch in the Division of Neuroscience at the NIA, are expensive. She and her peers are awaiting approval of plasma markers, which will make screening participants a lot quicker, in a trial and in the clinic. “We are heading in that direction…biomarkers are hugely important.”

That written, the NIA is using adaptive design in other areas. It is funding pilot studies with embedded pragmatic studies. But pragmatic studies have different roadblocks. Because these trials are based on wherever the data are gathered—patient’s home, doctor’s office, healthcare system—the reliance on EMRs is often frustrating.

This barrier of EMRs said Flanagan, is they weren’t originally designed to store patient data destined for clinical trials, they were created for billing purposes, so the data aren’t clean all
the time.

Federal regulatory and research institutions, here and abroad, have long been advocates, and often the underwriters, of trials with master protocol designs. In the early 2010s, the NCI and the UK’s National Institute for Health Research were funding a handful of trials.

 In the UK, the first master protocol approach—using multiple treatments against one control arm—was Stampede, which started recruiting in the mid- 2000s. The first basket trial that made the history books came in 2001 with the approval of Gleevec (imatinib).

Just recently, the FDA published its final guidance for master protocol-designed trials for COVID-19 treatments.

Stakeholders have at least one toe in the water. A 2019 review found that of 5,689 trials, dating to the early 2000s, 83 had umbrella, basket and platform designs. What was significant, the authors said, was that half of the trials had begun in the five years prior to the study.

During the early days of the pandemic, the NIH launched RADx, or Rapid Acceleration of Diagnostics, which propelled the COVID-19-testing collaborations between industry and regulators. By July 13, 2020, RADx received more than 600 applications. Within two months post-launch, 27 projects were in Phase I. As of May 2021, RADx was working with 33 companies.

The NIH is proposing creation of ARPA-H (Advanced Research Projects Agency for Health), similar to the RADx model. NIH Director Francis Collins spoke before the Senate Subcommittee on Health and Human Services in late May about the proposed $6.5 billion program. He said it will have project managers who partner with private businesses, big and small, and then “ride herd over these things carefully so that if they’re not doing well, they get basically stopped immediately.” It’s a high-risk project, he said, failures are likely, but the goal is to “identify the areas of greatest opportunity.”

Industry set to make choice on whether COVID-19 trials are the new standard.

Christine Bahls

Articles

‘Record’ Gains in Bringing Research Closer to the Patient

The Evolution of Site Selection

The Post-Pandemic CRO Landscape

The Future of Clinical Trial Design Looks Bright

The Many Paths of Diversity in Clinical Trials

Maximizing the Value of Remote Monitoring