Christine Bahls

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.

Articles

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 - 

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

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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.”

For Rea, linear trial design is nearly pointless. “The high failure rate that we’re seeing is because of the model which sees this as attrition. But the industry’s OK with it because some things make it through.”

Rea used the history of Cymbalta (duloxetine) to illustrate why repurposing Phase I and II is necessary. The FDA approved duloxetine in 2004 for treatment of depression, and has since approved six other indications, including diabetes-related neuropathic pain. Some 270-plus studies—from recruitment to completion—are listed in clinicaltrials.gov for many possible indications.

These approvals and new studies, said Rea, likely wouldn’t have come about if Eli Lilly, maker of duloxetine, had gone the traditional route, trial-design wise. Lilly looked at duloxetine “very broadly.”

In the beginning there were clues, he said, that this serotonin and norepinephrine reuptake inhibitor mitigated pain. “The interesting thing they did in Phase I/Phase II was to see what that effect in pain looked like.” The subsequent trial examined whether duloxetine worked in depression-related pain and non-depression-related pain. The results led to a Phase III on pain, which in a “traditional model would not have happened.” The endpoint would have been effect on depression, and nothing more.

“That kind of behavior is exquisite, because you’re using an early stage for what it is good for...finding out where the drug works.” Using the word “failure” he said, is counterproductive.

Flanagan said if trial investigators can get the data they need regarding safety and efficacy, they don’t need to do large Phase IIIs; Barry said the HER-2 positive trials are classic examples of not needing large Phase III trials.

Researchers new to using adaptive design should not wade into these waters without comprehensive instruction. “Knowing when and when not to adapt a trial, how to strategically plan for logistical challenges and how to conduct complicated interpretations are skills of the expert biostatistician, not the novice.”

Wrote Burnett et al.: Adaptive designs are not mainstream for many reasons, including the lack of expertise and experience among clinicians, trialists, and statisticians; design and analysis software; time to plan and analyze; and preferring the known to the unknown. The authors said they believe that investigators “aren’t clear as to what they are, what can be learned and how to apply them.”

The NIA, and others, are helping clear up these mysteries.

In 2020, the NIA began supporting a two-tiered program to train those who are needed to run these types of trials successfully. The programs, run out of University of Southern California, include instruction on diversity, both for the trial team and the enrollees, said Ryan. If study staff doesn’t represent the trial’s participants, it can impact enrollment, she said. The second tier of the program is for those current trial professionals who need to learn about biostatistics and other subjects. There is a whole range of professionals that make adaptive work, she said. The course is for graduate students, PhDs, MDs—the whole range of professionals.

“Medical and graduate schools, by and large, don’t offer this type of training,” Ryan said, an important reason why the NIA supports it. “This isn’t standard school training.”

Thomas J Hwang, Daniel Carpenter, Julie C Lauffenburger, Bo Wang. Failure of Investigational Drugs in Late-Stage Clinical Development and Publication of Trial Results. 

Nicholas S. Downing, Nilay D. Shah, Jenerius A. Aminawung, et al. Postmarket Safety Events Among Novel Therapeutics Approved by the US Food and Drug Administration Between 2001 and 2010. 

Laurie J Legocki, William J Meurer, Shirley Frederiksen, et al. Clinical trialist perspectives on the ethics of adaptive clinical trials: a mixed-methods analysis. 

A. Birtle, J. Barber. Ten Years on the Juggernaut Keeps on Rolling: Comments on the STAMPEDE Trial from the Front Line. 

Redman Mary W. Redman, Carmen J. Allegra. The Master Protocol Concept. 

https://www.fda.gov/news-events/press-announcements/fda-brief-fda-provides-guidance-master-protocols-evaluating-prevention-treatment-options-covid-19

Jay J. H Park, Ellie Siden, Michael J. Zoratti, et al. Systematic review of basket trials, umbrella trials, and platform trials: a landscape analysis of master protocols. 

Bruce J. Tromberg, Ph.D., Tara A. Schwetz, Ph.D., Eliseo J. Pérez-Stable, M.D., et al. Rapid Scaling Up of Covid-19 Diagnostic Testing in the United States — The NIH RADx Initiative. 

Testimony before Senate Subcommittee. May 26, 2021. 

Hana Mekonnen and Deborah Cole. White Paper: Understanding Adaptive Designs for Clinical Trials. NSF white paper. April 2020.

Thomas Burnett, Pavel Mozgunov, Philip Pallmann, et al. Adding flexibility to clinical trial designs: an example-based guide to the practical use of adaptive designs. 

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

The Future of Clinical Trial Design Looks Bright

Early in the 1900s, the medical world began to suspect that different types of people were more prone to specific diseases than their peers. As the century progressed, others outside the medical world began to get suspicious, too.

And when the world lost its semblance of sanity last March, as minority groups were dying from COVID-19 at higher rates than Caucasians, the world reacted; it called for real-world diversity in clinical trials and medical parity in the clinic.

 Studies were published, opinion pieces, too, even ads were aired for clinical trial equality.

 Page after page in Google can provide the details.

No doubt, the historical dominance of the white man as a trial enrollee has thwarted gathering evidence-based knowledge regarding the health and welfare of non-Caucasians. Without the latter’s participation in interventional trials, little can be ascertained as to whether the drug helped, hindered, or even hurt them. This lack of knowledge is acutely felt in the field of oncology. “Certain compounds affect certain populations,” said Diana Foster, PhD, vice president, Strategy and Special Projects, Society for Clinical Research Sites (SCRS). Diverse populations are “critical in drug development.”

To say that pharma has not paid attention to the problem of inclusion prior to the pandemic is inaccurate, those interviewed for this article said. An important point: inclusion can be defined in numerous ways, beyond the color of someone’s skin.

Diversity, said Joan A. Chambers, Senior Director, Marketing & Outreach, Center for Information & Study on Clinical Research Participation, is difficult to define. “It can go down many different paths.”

One such path is pharmacogenomics. The human body has about 30,000 genes, and each one, on average, produces three proteins. That’s a lot of opportunity for therapies to encounter genetic hiccups and disrupted metabolic pathways.

 Add to that how bodies are influenced by prior generations, and the world they are living in now. A 2013 study of 167 new-molecule-based therapies showed that one in five of them acted differently in minority groups, in different races and ethnicities.

“Diversity certainly has a higher profile now, but pharma began funding [our Diversity Site Assessment Tool project] four years ago,” said Foster. “Diversity is a scientific and conceptual issue that continues to evolve and develop.”

COVID-19 was not the impetus for pharma’s current focus on diversity in its trials, said Marie-Pierre Hellio Le Graverand, MD, DSc, PhD, senior vice president and Pfizer’s Clinical Development & Operations, Global Product Development lead. “We have been working on [minority inclusion] for a number of years. It takes time to move the needle.” Hellio Le Graverand and colleagues recently published Pfizer’s own clinical trial diversity track record for the last 10 years.

 The Pfizer representatives recently called for industry to address equity access to clinical trials.

But the pandemic made it clear that the world wants that needle to move and move fast.

Scientists began noticing differences among various groups, early on, starting in the late 19th century. (Mendel was growing and analyzing his peas around 1865.) In 1932, J.M. Adams wrote about the differences in blood pressure levels between a “group of white and [African American] workmen” in the American Journal of Medical Sciences.

Researchers then started reporting that different types of people react differently to medical therapies. In 1952, Hockwald et al. showed that red blood cells of 10% of African Americans and some Caucasians were fated for destruction if these patients were regularly given the antimalarial primaquine.

 In 1962, Tarlov et al. deemed the problem to be “an intrinsic abnormality of the erythrocyte,” as this “hypersusceptibility to hemolysis by drugs is a genetically transmitted inborn error of metabolism.”

FDA began its decades-long quest for inclusion in 1993, telling trial sponsors that if they wanted financial support for their clinical trials, they had to enroll other people besides young and middle-aged white males. Five years later, FDA got specific: break out the efficacy data according to the participants’ age, race, gender and ethnicity. With the first installment of the Human Genome Project a few years away, maybe the agency was gearing up to review precision-based medicines.

In 2001, J.F. Wilson et al. set out to see how drug response worked in participants from China, New Guinea, Sub-Saharan Africa and Western Eurasia. They were tested for shared genetic regions and then grouped with their genetic kinsman. Ultimately, the participants were put into four groups. Expecting to find the four groups geographically aligned as well, what they found was that geographically, borders don’t exist: Ethiopians joined people of Jewish descent, Afro-Caribbeans were, genetically speaking, neighbors of the West Eurasians. Human demographics are complex, the authors said, with no apparent natural clustering arrangement. The work does provide, they continued, a framework “for assessing the appropriate level of resolution in relating genetic structure to drug response.”

While FDA has approved and continues approving assay tests to ensure that the right medication, primarily for cancer patients, reaches the right genetic target, pharma’s long-running, one-size-fits-all approach was still in use.

In 2015, the CDER approved 45 new drugs with more than 105,000 patients enrolled. White people comprised 79% of that number, African Americans, 5% and Asians,12%.11 By 2019, African American participation had reached 11%, according to FDA figures.

This past February, an overview of 230-U.S.-located vaccine trials with 219,550 patients conducted between 2011 and 2020 showed both ethnic and racial underrepresentation. About 100 of the trial sponsors, or 58%, reported race; 79, or 34%, ethnicity.

In mid-May, another enrollment overview, this time of 207 U.S trials from 2007 to 2020 involving 8,429 pancreatic ductal adenocarcinoma patients showed that rates of enrollment for minority groups weren’t reflective of real-world, higher diagnostic rates.

The rates of somatic and germline mutations in Black patients differ from other racial subgroups, so their response to therapy also differs, said co-author Kelly Herremans.

 Black participants were less likely, at 2.9%, to be included in a Phase III trial than in Phases I and II, with each about 10%.

Just two more studies of note: In 2010 Booske et al. found that social circumstances, environment and genetics affected health by half;

 by 2016, the United Health Foundation found those three drove a person’s health by 60%.

In 2019, a study underwritten by Merck & Co. along with many stakeholders, including the Association of Black Cardiologists, Inc. and SCRS, surveyed cancer centers, looking for those more successful in recruiting racially and ethnically diverse patients than others. In essence, these centers found it takes informed, back-and-forth communication among all involved, while giving enrollees, their family and their referring physician more of a voice in making decisions. These sites also trained their investigators in cultural mores.

 Work on the Diversity Site Assessment Tool, now scientifically validated, began in 2016. Merck wanted help in finding non-Caucasian trial participants. “We consciously decided to approach the work scientifically,” Foster said. “What are the sites lacking, what do they know and what are we going to teach them?” Over the next four years, the group devised self-assessment surveys to get answers to these questions. Its financial supporters include pharma members and CROs.

Some sites don’t know their own communities, she said. “The site could be in an urban location, and three blocks behind the hospital is a huge population of Spanish-speaking people, and they don’t even know it.”

For the last survey, questions were sent to 437 sites located in hospitals, private physician offices that conduct trials and academic institutions and other research companies. Foster said SCRS will make the tool available; no specific training programs have been developed yet.

The targeted improvements pinpointed in the study are similar to findings in the 2019 Merck-funded study: locate minority-based organizations that can help build a network to find minority participants, like community centers, churches, support groups; include different languages on the phone prompt; and help participants get over hurdles, like finding housing should the patient need to visit a site, for himself and family.

Joan Chambers knows all about the hurdles of finding minorities for trials, and the need to use local organizations to find them. CISCRP has been minority focused since its founding in 2003. The goal has always been “how do we share this information about clinical trials in easy-to-understand content that does not sound scientific,” she said. The group disperses the information in the community, but it’s up to the recruitment arm to tailor the message for a specific study.

Local organizations can support gatherings at community centers or churches, and educate about clinical trials. And when they do, the questions that people ask at these gatherings all punch the holes as the studies geared to find
minority patients:

Does a participant have to know English to participate in clinical studies?

Can your primary care doctor refer you to a clinical trial?

What are trials, why are they important, who is involved?

At ZS, helping with minority recruitment is more about getting to the roots of “I won’t participate,” and “I won’t invite this person in.” ZS, a professional problem-solving firm, began its cognitive and behavioral science project six years ago. It has pharma sponsors, as does
Foster’s work.

The point of this project, said Jacob Braude, principal, is to identify the so-called mental shortcuts people take to make decisions, and to dismantle those shortcuts that prevent someone from enrolling in a trial, as well as those shortcuts that site coordinators and referring physicians take to discourage a would-be participant. Braude said academics have identified 100 such shortcuts. An example: A person with osteoporosis in her knee can get site injections four times a year. But this person only comes once, because her physician has told her, “Come back when there is significant pain.” This shortcut is called moral regulation in which the patient is balancing good and bad behavior. “We asked the patients, ‘do you have to earn your injection? and 60% said yes.’”

How COVID-19 blazed a new trail for greater patient inclusion.

Christine Bahls

Articles

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

The Road to True Data Harmonization