When Russian forces invaded Ukraine in late February of 2022, the world was searching for answers. Many industries and their respective markets were flipped completely upside down in a matter of weeks. Included is the clinical trials ecosystem in Ukraine—which has had a significant impact on trials globally as well.

 on the state of clinical trials in Ukraine. It reported that: “The field of clinical trials in Ukraine is currently suffering significant losses…hundreds of clinical trials have been disrupted.” The article also features research from GlobalData, which at the time, reported 502 trials were underway in the country.

Contract research organizations (CROs) and sponsors were now suddenly placed at the frontlines of a battle for clinical trials. Difficult logistical challenges rapidly unfolded, some of the most notable being the transport of critical supplies, communication with stakeholders outside of Ukraine, and most importantly, the safety of clinical research associates (CRAs) and patients.

In the face of adversity, one of the many organizations that stepped up to address these challenges was G1 Therapeutics. G1 is a biopharma company headquartered in Research Triangle Park, NC, that specializes in developing small-molecule therapies to address significant unmet needs in oncology. At the time of the invasion, G1 was executing trials in metastatic colorectal, bladder, and triple-negative breast cancers in Ukraine. The company was working with CROs IQVIA, Arensia, and Parexel on the trials. With the help of their CRO partners, G1 orchestrated the relocation of 12 patients to Poland, Moldova, Georgia, and Spain, where they are now continuing to receive cancer therapies.

Efforts to accommodate the patients began almost immediately after the war broke out. “We lost contact with our sites and with the CRA in the study,” says Anna Leblond, G1 clinical study lead. “We immediately had to make some critical decisions.”

One of those first decisions was getting therapies to the patients. With martial law having been instituted, couriers could not ship drugs to the sites from G1’s depot in Ukraine. Even if the drugs were needed right next door, it was impossible to ship due to strict regulations requiring controlled transfer. Several sites received shipments just prior to the invasion, but most did not. “Most of [the sites] ran out fairly quickly,” says Leblond. “[Around] April and May, we had a lot of sites that were using partial drug regimens or just not treating patients and hoping that they would be able to receive drug shipments soon.”

In addition to the immediate supply chain challenges, the violence unfolding around patients, sites, and CRAs quickly became a cause for concern. “We received reports from our CRO partners who had CRAs choosing to stay in the country and trying to text their sites from bomb shelters,” Jenn Warneke, SVP of clinical operations for G1, tells 

“Our first response was not about the trials; it was about the patients themselves. I think at that point, trial participation becomes incidental to safety. After that settled a bit, we started to think about, ‘okay, what does this mean relative to the clinical trial? How do we alleviate burden from the sites and how do we keep getting treatment to patients?’”

Warneke was impressed with the way the CROs handled the immediate chaos. Using their available local resources, the CROs were able to quickly mobilize their internal staff to help them get necessary supplies. There were CRAs who even elected to stay in Ukraine at the sites; some of them had to stay because of constraints relative to age, gender, and a potential call up to military duty, but others stayed because they wanted to help. “The people of Ukraine are incredibly resilient and determined,” says Warneke.

When it came to physically moving the patients out of Ukraine, the first step was finding sites in nearby countries that could accommodate them. Poland and Moldova were among the surrounding countries in which G1 had existing site relationships. The initial stages of planning came during a time when communication was almost impossible; it was mostly conducted through individual CRAs, as G1 had lost direct contact with sites. Leblond even recalls communicating via text message with a CRA who was in a bomb shelter for updates. Despite hurdles in communication, G1 made it clear to patients and investigators they had the option of leaving Ukraine, as they could not guarantee the shipment of therapies. According to Warneke, it couldn’t have happened without their CRO partners.

“CROs have incredibly broad reach, with local people in every country,” says Warneke. “It was remarkable how quickly CROs mobilized their internal staff and got them what they needed; the way they were able to communicate from the ground up.”

The language barrier was another significant area of concern for patients and sites alike. In the event patients had an adverse effect from treatment, they needed to be able to communicate that clearly. There were also different regulations and documentation required by other countries for clinical trials. Despite these initial challenges, the surrounding countries were able accommodate them. “Luckily, [the countries] were very understanding of the situation,” says Leblond. “It did take a lot of planning and getting documentation in place, but once that was secured, it was pretty straightforward. Everyone had the same goal of keeping patients safe and getting them access to the treatment they needed.”

While G1 paid for patients’ travel and, in many cases, their lodging, some logistical challenges—such as who they were going to stay with and how they were going to get across Ukrainian borders—were mostly out of their hands. Warneke recalls this as one of the scariest times in the process considering the uncertainty. “Every single time you heard that a patient made it, and they had connected with another clinic, we were really happy,” she tells 

. “We were constantly wondering, ‘Are they going to make it? Are they going to be able to get across [the border]? We don’t know what it was like; we only saw what was on the news and what we were hearing from our partners.”

Once the patients were safely situated, there were still challenges affecting the study and data collection. Due to patients missing doses, lapses in treatment, and site closures, G1 had to evaluate enrollment numbers and accelerate recruitment in surrounding countries to ensure quality data. However, data is still being tracked for patients who chose to relocate out of the Ukraine, and that helped reduce data gaps. “There was an impact, but we’ve been able to pivot enough to continue and follow through on these studies and meet our timelines and our objectives as needed for the study,” says Leblond.

Warneke shares the same sentiment that, once the logistical challenges were overcome, business was running as normally as it could considering the circumstances. “Once we got through the obstacles of the physical patient transfer, and then the logistics surrounding their journey to a new site for continued care, it really has been business as usual,” says Warneke. “Very few patients were lost to follow-up during this period of time.”

While the pandemic and the war in Ukraine have been unprecedented challenges for global trials, they have served to strengthen the industry’s approach to clinical research and patient care. From virtual site visits to remote monitoring to wearable devices, trials have rapidly adopted new technology to bring studies to patients, rather than patients to sites. Likewise, companies are recruiting more diverse individuals to ensure that study data accurately reflect the populations their drugs will treat. Countries like Ukraine are welcoming these opportunities, and they have ample staff to accommodate them—until recently.

“There are always more considerations when initiating global trials due to cultural, regulatory, procedural, and language differences,” says Leblond. “We were willing to take the risk, knowing what we knew. “[But] if we knew this was going to happen, absolutely not. Everybody lost money, time, data, and—most importantly—patients were in danger and temporarily lost access to critical drugs.”

Looking forward, there are lessons to be learned from this experience. “One of the biggest things during a debrief after a crisis or challenge is to try and anticipate and mitigate risks for future protocols and study start-ups,” says Warneke. “This teaches us to build in mitigations maybe a little bit sooner, and to assess the global landscape so we’re prepared to pivot more quickly.”

Warneke also hopes that G1’s work serves as a beacon of hope for industry in difficult times. “It makes me realize that we’re really a lot smaller globally than we think we are,” she says. “When we need to come together, we do. It renews my faith. It adds another foundational brick that, in my sense, in this industry we are all out to do good. We create a solution, no matter what situation we find ourselves in.”

is Associate Editor of Applied Clinical Trials. He can be reached at

Articles

Feature Articles

Ukraine invasion tests the resiliency and quick action of CROs and sponsors.

Mobilizing and Maintaining Clinical Trials in Midst of War

Let’s discuss—no, parse—the impact of inflation on clinical trials. Will each type of stakeholder contract equally, or will one segment be affected more than the others? How much contraction has already taken place? The trial world has ongoing serious problems, such as finding enough qualified staff to run a trial and working within the approved schedule to complete it. Staff shortages and time delays already impact budgets without inflationary help.

A larger question is whether inflation will alter, as the pandemic did, the design and production of these studies. Hints that this could happen are popping up: trial designs considered more efficient and adaptive, for example, are showing up more frequently in ClinicalTrials.gov; data discussed at the recent DPharm conference in Boston showed a majority of sponsors were incorporating decentralized trial (DCT) components into their studies.

Another pivotal question is whether sponsors will pull back on running global trials. It won’t happen, believes David Fenske, principal, delivery and client advisory, Auxilius. Regulatory bodies want trials to run in their countries; the FDA wants diversity; and if it is a rare disease trial, “there are only so many patients in rare diseases,” he says. “You have to go where the patients are.”

However, inflation will affect the outlook, operations and possibly the existence of smaller biotech firms; money, used for a mortgage or biotech startup, is no longer cheap. Those with one, maybe two, promising therapies in their portfolios will be absorbed, bought, or left behind. From a societal point of view, being overlooked is okay if you make sneakers, but not if that product has the potential to cure amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, or some other condition with a death sentence.

As a whole, no one interviewed for this article said the clinical trials world has met its demise. What has emerged from conversations and document reviews, including Q2 earnings reports, are industry viewpoints seen from macro and micro levels: industry is resilient, yes, but the cost of packaging and mailing temperature-sensitive samples from overseas could reduce the number of countries or sites involved in a trial. Anything that changes the costs of goods, says Jane Myles, vice president of clinical trials innovation at Curebase, will affect one or more aspects of the trial.

“Clinical trials are logistical puzzles,” Myles tells 

 The importation and exportation of samples are huge costs. Pharmacokinetic (PK) samples are fragile and maintaining that fragility “costs a lot of money,” she adds.

As do startups. With investment capital flowing more slowly, “the risk [of shutting down] is magnified if you are smaller,” says Sharon Langan, vice president, channel and strategic partnerships, Auxilius.

Before a sponsor will jettison a project, it will focus on increasing opportunities to drive project efficiency and the decentralized better monitoring that grew out of the pandemic, according to Craig Lipset, founder of the Decentralized Trials & Research Alliance. “I haven’t seen sponsors deprioritize entire development programs” he says. But inflation will be real, he continues: “As inflation drives up everything on a global basis, as those costs increase…[sponsors] may have to reduce the number of trials for next year.”

As for a possible recession, the clinical trial industry should be concerned, notes Justin Culbertson, life sciences senior analyst, RSM US LLP. The industry is experiencing capital funding slowdowns and extremely high labor demand—“which means [higher] wages, and it will cost more to bring a drug to market,” he says.

The No. 1 affected stakeholder, Culbertson believes, will be the consumer, should trials be axed. Deciding what nascent trial to eliminate will be difficult for the survival of a more mature one, adds Ken Getz, director of the Tufts Center for the Study of Drug Development (CSDD).

But reducing trial numbers, from the strict vantage point of the industry itself, may not be a bad thing, considering the record-number of studies ready to go and the lack of qualified staff to run them.

 quoted analysts saying the pharmaceutical index was gaining because pharma can “weather recessions relatively well.”

That doesn’t mean drug manufacturers won’t take a hit: in mid-October, the index’s year- over-year was 893.97 vs. 769.48.

In IQVIA’s second-quarter earnings call, Ari Bousbib, its chairman and CEO, said his company and the contract research organization (CRO) industry at large were, financially speaking, a hardy bunch.

 “During the recessionary times over the past two decades, annual S&P 500 revenue contracted by as much as 10%, while IQVIA’s clinical business and the CRO industry as a whole never experienced a year of revenue decline,” he said.

As of this writing, the US is facing—not in—a recession. A few figures to consider: The Bureau of Labor Statistics’ Producer Price Index

shows that, from September 2021 to September 2022 the costs to businesses of basic inorganic chemicals rose 28.8%; basic organic chemicals rose 7%. Paper boxes and containers were up 19%; plastic packaging, 12.9%; water transportation, 27.9%; warehousing, 7.9%; and traveler accommodation services, 17.7%.

As for stock performance, the year-over-year changes for six of the larger CROs are all southbound, some more significantly than others. One organization dropped to 173.9 from a high of 313; another to 48.19 from a high of 194.18. Many are buying back stock shares, presumably to bolster stockholder value.

GlobalData reported that pharma had a month-on-month dip of 2% from July into August, but job postings went up 10% during the month.

The Council for Insurance Agents and Brokers, generally speaking, said premiums for cybersecurity in Q1 2022 rose an average of 27.5%, slightly higher than during the same period last year.

As for salaries and staff turnovers, this publication discussed those issues earlier this year. It found that average turnover for clinical trial professionals, especially for the lower paid but critical position of coordinators, was 26%. As for salaries, the differences between manager and associate coordinators, as compared to site directors, ranges from a high of $75,000 for the former, and $250,000, for the latter.

According to RSM research, in 2016 a Phase III, biologics trial took 2.5 years to complete (based on 94 studies); a drug study, 2.6 years (608 studies). By 2021, excluding COVID-19 studies, a biologic study took 3.3 years (85 studies) and a drug study, close to 3.5 years to complete (435 studies).

“Only 46% of Phase III studies started over the past five years reported having met enrollment requirements,” the report said, attributing most of these lag times to significant labor shortages at investigative sites.

Q2 earnings reports showed pass-throughs are on the high side: 20% of revenue for one company, another was $46 million above the unmentioned guidance range midpoint. Interest rates, discussed in one report, were already $50 million above the initial figures given in the company’s January guidance. The adjusted figure for the year was $210 million.

As for global digital health funding, the drop is remarkable—36% in Q1, according to CB Insights.

Langan said Auxilius recently surveyed biotech organizations across the sector; she says 93% experienced site costs out of line with initial per-patient cost projections. The majority of respondents indicated they struggle with estimating clinical trial accrued expenses, in part due to variability in actual cost drivers.

Over the past five to seven years, Fenske says, investigator budgets “would go out 50%. Now I have seen that shift starting at the 75% percentile.” Sites are “being squeezed with staffing” and that is limiting the number of trials, he adds.

Tufts CSDD’s Getz started analyzing clinical trials in a scholarly way more than three decades ago. Since then, the US experienced at least four recessions. Getz notes that economic pressures constantly weigh down on sponsors, CROs, and vendors. So inflation, 

doesn’t stop a sponsor from continuing a clinical trial or reducing the number of patients.

Sponsors, says Getz, have a way of responding to these pressures. Full-time equivalents might be replaced with more outsourcing. They can downsize, consolidate, and can turn to digital tools, he points out.

“It’s not sort of a linear this, then, that,” Getz tells 

. The pressure, he believes, will be on the CROs to follow the trial model and streamline the costs—which can be very difficult, say, with an oncology trial being conducted in numerous countries. Along with difficulty in finding patients, “most of these trials require DNA samples,’’ adds Getz.

While these difficulties extend timelines, these factors are not the primary cause of the extensions. “Our research shows that it is too difficult to determine what the individual factor is extending cycle time,” says Getz. “All of our trials are taking longer. So [any] argument that inflation will delay treatments getting into the marketplace isn’t supported by hard evidence.”

But they won’t get to market if there is no trial. “The CROs were saying a year ago they didn’t have enough people,” says Culbertson, adding that he thought there were too many trials “because [CROs] don’t have enough people to work on them.”

To put the industry’s labor shortage in perspective, Culbertson notes that the life sciences labor market returned to its pre-pandemic level one year ahead of the rest of the country, which took two years. But demand and inflation are driving up wages. RSM research shows that the unemployment rate would have to reach a minimum of 4.6% to start getting inflation under control, he says, so either reduce demand for research or increase available workers —but something has to give, Culbertson adds.

The demand for research, at least in oncology, isn’t shrinking. Recent data show grant applications to NIH’s National Cancer Institute (NCI) are up more than 50% as compared to about 5% for the agency’s other institutes.

Small biotechnology companies, and even more established ones, are facing a contracting capital market that is holding back investment dollars. “That capital will not stretch” to cover all trials out there, says Lipset. Will they sell to large pharma, will they make deals with smaller firms?

The big organizations will be scooping up those “biotechs that are hurting,” and the firms with just one product in their pipeline aren’t likely to start any trials, adds Fenske.

According to Culbertson, biopharma is already reacting to market forces. “We are seeing hesitancy picking next products, seeing more desire to negotiate prices,” he says. But he also noted that even though clinical trials are costing more money, if a trial is still running once the market reopens, that sponsor could secure more funding and finish the study.

Getz strikes an optimistic note, explaining that when a developer has a great molecule, one would be surprised how it can find merger opportunities. His research, he points out, hasn’t shown evidence of a mass exodus of biotech firms. “They find other ways to adapt,” says Getz.

Fenske was asked if there is wiggle room within trial phases to see what could be cut. In Phase I, there is not a lot of give and take in a negotiation, with the volunteers from healthy populations. The CROs have it down to lunch for $8 and dinner for $12. There is no place to cut dinner. But some agreement terms can be adjusted. Fenske had one sponsor client who objected to paying the CRO 100% upfront for a six-month Phase I trial. However, the sponsor CEO said give the CRO 10%—with 30 days to pay; they eventually compromised to 25%.

The CRO wasn’t being unreasonable and the sponsor prevailed. But now, in current master services agreements, the payment window is much shorter and the upfront money is paid in 10 days.

Phase II is more flexible, says Fenske. And while there isn’t “a lot of slush” in there, if this part of the trial has 75 patients and eight sites, for instance, Fenske suggests reduce the number of sites and increase the number of patients per site. Another place to cut would be to reduce the number of face-to-face meetings with the sponsor. A meeting every six months on an 18-month trial isn’t necessary, says Fenske. Another possible time saver is to adapt the monitoring plan from a former trial. Fenske notes he regularly reviews costs from previous studies.

CROs do not regularly review prior study costs, he adds, as such a review depends on how much time the sponsor gives the CRO to put together the proposal. “Sponsors are shooting themselves in the foot, when they say ‘we need it in 10 days,’ says Fenske. “They are not giving the CROs enough time” to build the budget more efficiently. But CROs have run thousands of studies, the sponsor likely just a few. Ideally, the sponsor should say to the CRO, “‘Here are the endpoints I want, you go design the study, we will agree on the price and the risk is on you,” explains Fenske.

A Tufts CSDD study found that in the long run, DCT components used in Phases II and III can save time—perhaps three months each—and money, with a seven-fold ROI. The study found reductions in screen failure rates and in the number of protocol amendments when decentralized components are in use.

That time-savings, says Curebase’s Myles, is vital. If the DCT model can save six months between the last patient out and data becoming accessible, “that is huge,” she notes.

But, cautions Myles, planning a DCT can be complicated. The trial team, she says, has to consider how the components are distributed: Some patients may want to visit a brick and mortar site, others like being at home, and those visiting nurses are earning more these days. Not everything happens in the cloud, reminds Myles. Another consideration is the investigator grant—it won’t extend to at-home visitation. “The doctor isn’t paid for what happens in the home,” says Myles. Investigators will be paid for oversight and data review of patients. “It is more a distribution of costs over a broader network,” she adds.

In the long run, according to Getz, these new solutions and tools indicate opportunity in the research enterprise, pointing to artificial intelligence, augmented and risk-based analytics, and new protocol designs. ClinicalTrials.gov listed 32 active interventional adaptive design studies, and 79 enrolling as of Oct. 11. “All of these things are new innovations that can improve on and address economic pressures,” he says.

, Freelance Writer for Medical, Clinical Trials, and Pharma Information

David Wainer. Pharma Is Place to Hide During Recession. 

https://www.wsj.com/articles/pharma-is-place-to-hide-during-recession-11657749897

IQVIA Holdings, Inc. (IQV) Q2 2022 Earnings Call Transcript | 

Bureau of Labor Statistics. September 2022. 

https://www.bls.gov/news.release/pdf/ppi.pdf

World Economy News. GlobalData finds continuous layoffs amid sizable decline in active, posted, closed jobs | Hellenic Shipping News Worldwide. Sept. 9, 2022.

Commercial Lines Market Trends Report–Q1 2022 | Property & Casualty. 

https://www.cbiz.com/insights/articles/article-details/commercial-lines-market-trends-reportq1-2022-property-casualty

Commercial Property/Casualty Market Index. Q2/2021. Q2 P/C Market Survey 2021.

Lisa Henderson. Salary Survey: The Age of COVID. 

https://www.appliedclinicaltrialsonline.com/view/salary-survey-the-age-of-covid

Justin Culbertson. Life sciences services trends and outlook: Fall 2022. 

https://rsmus.com/insights/industries/life-sciences/clinical-trials-trends.html

Research Report. State of Digital Health Q1’22 report. 

https://www.cbinsights.com/research/report/digital-health-trends-q1-2022

Experts gauge threat level for global trials amid staffing and funding issues.

The Implications of Inflation for Drug Development

Because the numeric rating scale (NRS) and visual analog scale (VAS) are frequently used in clinical outcome assessments (COAs), these (along with the verbal rating scale, which is not addressed here) are commonly migrated to electronic devices for use by trial participants to collect endpoint data. Despite their prevalence and the existence of migration best practice recommendations,

 we frequently see suboptimal implementation of these response scale types that could compromise a measure’s psychometric properties and trial outcomes. This article is a primer on the implementation of the NRS and VAS on eCOA systems and includes tips for ensuring your eCOA provider can accommodate best practice recommendations.

An NRS consists of numbers representing an ordered continuum of some attribute. The NRS typically includes verbal descriptors/anchors at the ends. Respondents select the number that reflects their perceived state.

FDA’s patient-reported outcomes (PRO) guidance

 defines the VAS as a line of a fixed length (on paper, typically 100mm; eCOA uses 101 distinct response points, regardless of line length), with verbal anchors at the extreme ends, and no descriptors of the scale’s intermediate positions. Typically, no numbers are presented at the anchor positions. Respondents are asked to place a mark on the line corresponding to their perceived state.

While both NRS and VAS have been used in endpoint measures to support labeling claims,

 suggests superiority of NRS over VAS in pain measures due to ease of administration and scoring, higher acceptability, and psychometric property retention. Further, while FDA guidance suggested VRS, VAS, and NRS are all suitable to measure pain,

 states the NRS is the most appropriate measure of pain intensity. In fact, FDA’s Patient-Focused Drug Development draft guidance

 states that FDA does not recommend the use of a VAS.

 These regulatory recommendations, as well as concern about VAS comprehension, are reasons why novel instrument developers may select other response scales over the VAS. Finally, the Critical Path Institute’s (C-Path’s) PRO Consortium recommends avoiding the VAS when developing 

 PRO measures and encourages use of other response scales appropriate to the measure’s content and the patient population.

Regardless, because both NRS and VAS are frequently used in COAs and need to be implemented in eCOA solutions, it is imperative to follow best practice recommendations for faithful migration to retain a scale’s measurement properties. Figure 1 below shows examples of an NRS and VAS that align with best practice recommendations.

Can your eCOA provider follow best practice recommendations?

Although VAS and NRS are common, some eCOA providers struggle to implement them according to best practice recommendations and offer unacceptable suggestions and/or formatting (e.g., NRS response options wrapped over multiple lines), incorrectly insisting that VAS lines must be 100mm long despite extensive comparability evidence,

 and displaying numeric values associated with a VAS response. In part, eCOA providers should be assessed based on the provider’s study-design capabilities.

Sponsors are urged to choose providers who demonstrate their system’s ability to accommodate complex designs, conditional logic, a user-friendly interface, and faithfully migrated measures. Sponsors are cautioned to scrutinize the capabilities of providers with no proven experience in eCOA data collection in clinical trials who propose non-clinical, generic data capture systems such as commercial online survey tools to capture eCOA data. The functionality required to display scales according to best practice recommendations, let alone complex solution design or custom report generation, is often not available in those generic systems. Those basic limitations could lead to deviations from eCOA best practice recommendations and result in low-quality data that compromises trial outcomes.

Ensuring your eCOA provider is aware of and has experience in implementing eCOA best practice recommendations is pivotal to collecting data that appropriately measures endpoints and withstands regulatory scrutiny.

Authored on behalf of Critical Path Institute’s eCOA Consortium by 

, Vice President, eCOA Science, YPrime; and 

ePRO Consortium. Best Practices for Electronic Implementation of Response Scales for Patient-Reported Outcome Measures. Available at 

https://c-path.org/programs/ecoac/epro-overview/best-practice-documents

Electronic Patient-Reported Outcome Measures: An Implementation Handbook For Clinical Research

Mowlem, F.D.; Elash, C.A.; Dumais, K.M.; Haenel, E.; Olt, J.; Kalpadakis-Smith, A.V.; James, B.; O’Donohoe, P.; Balestrieri, G.; Becker, K.;. Newara, M.C.; Kern, S. on behalf of the Electronic Clinical Outcome Assessment (eCOA) Consortium. Best Practices for Paper to Electronic Migration of Patient-Reported Outcome Measures. Manuscript in preparation.

Haefeli, M.; Elfering, A. Pain assessment. 

 15, Suppl 1(Suppl 1): S17-24 (2006). doi: 10.1007/s00586-005-1044-x. Epub 2005 Dec 1. PMID: 16320034; PMCID: PMC3454549.

U.S. Food and Drug Administration. Guidance for Industry Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. 2009. Available at 

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/patient-reported-outcome-measures-use-medical-product-development-support-labeling-claims

Gnanasakthy, A.; Mordin, M.; Clark, M. A Review of Patient-Reported Outcome Labels in the United States: 2006 to 2010. 

Gnanasakthy, A.; Mordin, M.; Evans E. A Review of Patient-Reported Outcome Labeling in the United States (2011–2015). 

Gnanasakthy, A.; Norcross, L.; DeMuro Romano, C.; Carson RT. A Review of Patient-Reported Outcome Labeling of FDA-Approved New Drugs (2016-2020): Counts, Categories, and Comprehensibility. 

 25(4), 647-655 (2022). doi: 10.1016/j.jval.2021.10.006. Epub 2021 Dec 24. PMID: 35365309.

Safikhani, S.; Gries, K.S.; Trudeau, J.J; Reasner, D.; Rudell, K.; Coons, S.J.; Bush, E.N.; Hanlon, J.; Abraham, L.; Vernon, M. Response scale selection in adult pain measures: Results from a literature review. 

https://doi.org/ 10.1186/s41687-018-0053-6

U.S. Food and Drug Administration. Guidance for Industry Analgesic Indications: Developing Drug and Biological Products. Draft Guidance. 2014. Available at 

https://www.fdanews.com/ext/resources/files/02/02-05-14-Analgesic.pdf

U.S. Food and Drug Administration. Development of Non-Opioid Analgesics for Acute Pain; Draft Guidance for Industry. 2022. Available at 

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/development-non-opioid-analgesics-acute-pain-draft-guidance-industry

Celeste A. Elash. Personal communication.

U.S. Food and Drug Administration. Patient-Focused Drug Development: Selecting, Developing, or Modifying Fit-for-Purpose Clinical Outcome Assessments. 2022. Available at 

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/patient-focused-drug-development-selecting-developing-or-modifying-fit-purpose-clinical-outcome

Byrom, B.; Elash, C. A.; Eremenco, S.; Bodart, S.; Muehlhausen, W.; Platko, J. V.; Watson, C; Howry, C. Measurement Comparability of Electronic and Paper Administration of Visual Analogue Scales: A Review of Published Studies. 

Therapeutic Innovation & Regulatory Science

https://doi.org/10.1007/s43441-022-00376-2

Data Collection

Despite prevalent use in electronic devices, NRS and VAS are often implemented suboptimally. 

Implementing Numeric Rating and Visual Analog Scales in an eCOA Solution

Debate on tackling rare diseases is reaching a fever pitch in Europe as expectations mount over the upcoming changes to European pharmaceutical legislation. Hardly a week goes by without a patient group, a scientific society, a European Parliament committee, an industry association, or a coalition of stakeholders staging a rare diseases event to press its particular priorities for better provision within European healthcare systems. The consequence is a flood of rhetoric about common interests and joint programs on everything from clinical trials to research incentives. But innumerable sharp differences on specifics are easily discernible among the tide of earnest declarations.

Patients are naturally among the most vocal advocates of improvement, with repeated evocations of the huge cumulative numbers. Official figures indicate 36 million people in the EU live with a rare disease, and there are more than 6,000 distinct rare diseases in the EU, of which most are of genetic origin (and most of them manifest in childhood). Patients want more and better research into diagnostics and therapies, and they want easier and faster access to the products that emerge. But even among patients, the needs of each group differ, and tough choices are going to be necessary over whether to prioritize old or young populations, ultra-rare or widely burdensome diseases, or conditions that cost the economy the most.

Policymakers and government are starting to recognize more clearly that there are risks—in terms of health and of practical politics—in neglecting such a large segment of the population. Gently pushed by European Union recommendations over the last decade, they have begun to put in place measures both to create national rare disease plans and to pool scarce resources spread across the EU, enabling patients and professionals to share expertise and information. But governments are also confronted increasingly with the challenges of paying for some of the dramatically more expensive rare disease therapies now coming onto the market, with poorer countries pushing for assistance in procurement, while health campaigners and other civil society organizations are openly skeptical of the value that drug firms claim for many of these medicines.

The pharmaceutical industry has also, inevitably, been prominent in the discussions, consistently highlighting the potential of new approaches to research and development and arguing forcefully for a regulatory environment that encourages and is prepared to incorporate innovation into healthcare. The industry’s characteristic expressions of optimism are colored more darkly by repeated premonitions of declining competitiveness in the face of an unhelpful operating context, and by rejection of what some companies see as simplistic one-size-fits-all approaches to promoting patient access.

Now all these stakeholders are confronted simultaneously with these questions of promoting innovation, overcoming inequities in access, and balancing healthcare budgets, as the revision of the EU laws is expected to finally get underway in 2023. This legislative marathon will cover not just pharmaceuticals in general, but also the rules specific to orphan drugs and pediatric medicines. In the run-up to this major rewrite, EU member states are showing a new degree of energy in promoting debate on rare diseases, with coordinated conferences among France, Czechia, and Sweden—the last, the current, and the future holders of the rotating six-month presidencies of the EU council of health ministers.

The received view is that cooperation, collaboration, and dialogue can resolve the innate divergences of view among the different stakeholders—and the spirit of the EU itself, built as it is on decades of compromise in the common interest, is repeatedly invoked as a clarion call. There is much to be gained from working together, particularly on rare diseases, where patients (and relevant expertise) tend to be widely scattered across countries. But industry’s calls for making the EU more attractive for investors and for the introduction of a streamlined and flexible approvals system are running headlong into regulators’ hesitations over the use of real-world evidence and accelerated pathways, into payers’ resistance to high price tags for unproven therapies, and into patients’ concerns that many needs are still going unmet and many treatments are available only to restricted populations.

Hard not to ponder whether Nathalie Moll, director general of the European Federation of Pharmaceutical Industries and Associations (EFPIA), the main industry group, was expressing confidence or concern when she remarked at the end of October: “I hope that the revision of the pharma legislation can be a catalyst for Europe to shake the access-vs.-innovation dogma.”

View from Brussels

Rare disease stakeholders speak out ahead of anticipated EU changes.

‘Dogma’ About Innovation vs. Access Impeding EU Fixes for Rare Diseases

There is a lot of talk about money. Inflation, recession, interest rates, which we feel most directly in our trips to the grocery store, going to events, or just keeping our cars running. All of this makes people anxious, and, in turn, serves to reinforce the negative churn in the markets. In this issue of 

, our main feature discusses inflation in relation to running global clinical trials. And indicators are, yes, around inflation, funding, and investment, but as a short-term problem. In the long-term, global clinical trials are not in danger of slowing down.

Other trends in clinical trials are signaling longer-term fiscal impact. Let’s look at the pandemic. While its silver lining was a forced pivot to decentralized trials, DCTs still have an aura of the unknown. Which technologies should be implemented? How are sites going to be trained or compensated for technological shifts? If participants are mostly monitored at home, how does that shift clinical trial agreements and contracts? But also, when does the use of technology in DCTs become a burden to patients?

Another long-standing debit in the clinical trials industry is the cost of low participant enrollment and retention in clinical trials. But if patient centricity becomes patient burden, it causes a deficit with patients themselves. If data is the currency in clinical trials, then patients are the medium. As a finite resource, participant time and emotional investment into a clinical trial is immeasurable and should not be idly wasted.

For a long time, industry was accused of not considering participants at all in clinical trials, and the patient-centric movement was born. Recent discussions with veteran industry professionals indicate a real desire to move away from overt patient burden in the guise of centricity, and into the reality of clinical trial participation.

Even a pharma CEO recently noted that sometimes, patients just don’t want all eyes focused on them. They just want to live their lives. And feel the same anxieties we all do.

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

From the Editor

Industry experts reinforce not putting all eyes on the patient.

When Does Patient Centricity Equal Burden? 

Issue PDF

Click the title above for a link to open the Applied Clinical Trials November 2022 issue in an interactive PDF format.

Applied Clinical Trials November 2022 Issue (PDF)

In 2016, a diverse group of researchers came together to publish the FAIR Data Principles. Their goal? To push science further, faster by improving the infrastructure supporting the reuse of scholarly data. The FAIR principles call for proper data management to speed up knowledge gathering and propel innovation forward. 

, the guidelines provide key requirements to make scientific data FAIR—findable, accessible, interoperable and reusable.

As clinical trials increase in data volume and complexity, the FAIR principles and guidelines have been widely adopted since publication. FAIR is a core element and driver for the digital transformation of drug development and life sciences R&D. Here’s what to know about the current adoption of FAIR principles in clinical research today.

FAIR is not a standard and the principles offer no explicit guidance on how researchers should use the procedures for FAIRification. Many different approaches exist regarding how to FAIRify data. In order to guide researchers during the process, 

 have been developed and published. These include: 

A generic workflow for the data FAIRification process

From raw data to FAIR data: The FAIRification workflow for health research

, both published in 2020. Most of the steps in these workflows, however, require specific types of expertise. To ensure that the steps are properly executed, they should be carried out by a multidisciplinary team under the guidance of FAIR data stewards as opposed to individual researchers.

To ‘become more FAIR,’ one needs to make sure that collected data and associated metadata are both readable for humans (the study team or other researchers that might want to reuse the data) and machines (algorithms that process and analyze the data). Therefore, when incorporating the FAIR principles into a new trial’s setup, specific emphasis should be placed on amplifying the ability of machines to find and use data automatically—while supporting data's ability to be reused by individuals.

Last year, a team of researchers at Castor and Amsterdam UMC set out to get a reading on the industry’s perception and acceptance of FAIR. A questionnaire was distributed to researchers and support staff across six Dutch University Medical Centers and users of Castor EDC. The questionnaire assessed the individual’s perceptions and behavior concerning the FAIR Data Principles.

, which showed that 62.8% of researchers and 81.0% of support staff are currently putting forth some effort to achieve any aspect of FAIR (findability, accessibility, interoperability, or reusability). The research found that less than half of the researchers add metadata to their datasets. Less than 40% add metadata to data elements, and just over a third deposit their data in a repository. Only 11% of the researchers and less than 25% of the support staff address all aspects of FAIR.

Of those surveyed, just over 1 in 3 researchers said that they can make their data more FAIR on their own. But if they received help to follow the principles more closely, more than 4 in 5 researchers reported success. This statistic confirmed researchers are willing to make their data FAIR if they received the right resources—but more help is needed to further implement the FAIRification approach.

One of the study's most interesting statistics revealed that almost 95% of researchers are aware of the usefulness of their data being FAIR for others. Even more interesting was that almost 90% are willing to FAIRify their data—given the right resources and support. The critical resources needed? Help from experts, budget, and time.

The study showed that when researchers are required to spend their own money and time on the FAIRification process, their intention and motivation significantly decrease. The industry needs to increase awareness of the short-term and long-term value of FAIR data and metadata and take the principles into account when planning (and budgeting) future studies. More help from institutions and funders is required to develop FAIRification training and tools. They also can financially support researchers and staff throughout the process. They could also appoint support staff and semantic data experts to help researchers with the FAIRification process.

If study teams think of FAIRification before they start a trial—and then receive the support they need to make their data FAIR—future research will be fueled by human- and machine-readable data and metadata. That data can be re-used by others and combined with other data, leading to exciting new insights. FAIRification therefore holds the promise of revolutionizing research science and greatly benefiting the entire research community and patients worldwide.

, PhD, assistant professor in medical informatics at Amsterdam University Medical Centers and a product owner at Castor

A Closing Thought

Study shows more support is needed for clinical teams to ‘FAIRify’ their data.

The State of Data FAIRification in Clinical Research

Clinical trial quality has changed after the pandemic. Sponsors are following new regulatory guidances on creating a “culture of quality,” and having access to near real-time data are revealing novel ways of overseeing clinical trials. Sheri Kuss, clinical quality group lead at Pfizer, evangelized her perspectives at Momentum Events’ Clinical Quality Oversight Forum.

Moe Alsumidaie: How has clinical trial quality changed in today’s environment?

 Risk management and quality tolerance limits (QTLs) are critical areas of discussion. I'm impacted daily by the speed of science, and I think we've all benefited from it, but how do we demonstrate oversight? Auditors like to look at events and their root causes. Do we have a process? Do we have a strong, robust quality management system, training SOPs, risk management plan development, and quality tolerance limits? Looking at study conduct to see if there is noise or real quality concerns is vital in today's environment because you have to answer these questions rapidly and comprehensively. Having near real-time access to data helps immensely.

 We look at quality events related to subject safety, subject rights, and data integrity. Triaged into different levels, levels 2 and 3 get cross-functional team investigations, and I attend these events to monitor trends and risks. I look at trends, quality events, and audit findings to connect dots and share information broadly. Everyone knows and owns quality, so it’s certainly embedded in our culture. Still, in our meetings, my ears perk up every time I hear my colleagues mention risk. Of course, not all risks are created equal, so I have to distinguish between operational and quality risks. We often build storyboards for our more complex issues and these storyboards stay behind the scenes. We're not just focusing on particular issues, we are evaluating whether the problems are systemic and if the CAPAs are effective. We also try to improve on efficiency whenever possible: as an example, we maintain the same team members when investigating events since they have built a knowledge base regarding the study.

When it comes to risk management, one of the things that we've done well is that we're bringing risk management issues up daily and/or weekly and talking about them and the potential cross-functional impact. We start by focusing on the following: what's a risk for the study, what is the potential impact, and can we mitigate it effectively? Quality professionals are conservative, and we are risk-averse typically. When working at light speed, the best thing to do is to get in front of the risks before they become issues, if possible. Naturally, you can't stop all events from happening. Still, if you're looking at risks across the board, there will be ambiguities, and it is critical to investigate and question these ambiguities on a more granular level. We've challenged and adapted our risk management plans several times throughout the life cycle of a study because we want to get it right. These are often impacted by protocol amendments, quality events, deviations, and the region's risk level, to name a few.

MA: How has the pandemic impacted perspectives on quality?

 We were very conservative, given the pandemic-driven virtual situation we were in, which was a good mindset to have, especially since there were so many unknowns at the time. We put prospective control measures in place cross-functionally and kept open lines of communication. I'm especially impressed with our teams' performance and engagement throughout the risk management process. For example, our teams give a lot of thought about study design as it pertains to quality elements such as participant participation and compliance. The study design and participant experience must be talked through so that risks can be evaluated rigorously.

MA: Do QTLs have to be adjusted when amending protocols?

 QTLs have to be closely monitored during the study and adjustments may be needed, especially when a protocol amendment is issued. A significant compliance risk is when there are multiple protocol amendments within a study, which potentially has many complicating factors. It is naïve to think that amendments are issued with minimal impact to study conduct, documentation, compliance, and monitoring of data. The reality is that downstream effects potentially could be enormous. For example, just related to QTLs, you may have to adjust the QTL parameter, definition, threshold, monitoring of them and possibly the mitigations based on the changes.And, if it's not clearly documented, then it could be a question internally or with regulators. We need to get in front of anticipated risks by building tools, tips, having access to near real-time data, sharing lessons learned and creating storyboards.The more we can do these things prospectively and share lessons learned from similar situations or studies, the better off we are.

MA: How has near real-time access to data changed clinical trial quality oversight?

 We have a custom-built dashboard focused on Quality data. This dashboard has historical and near real-time data. Accessing a dashboard with up-to-date data at my fingertips has been transformative. Connecting dots early has been impactful in programs that run quickly. I examine events and look for potential trends. If we have that data, we can mitigate risks much faster. Very simply, if something happened at one site and seems as if it could happen elsewhere, I'll share it and ask if we have strong enough mitigations to prevent it from happening more broadly. If we can apply mitigations broadly, then our CAPAs could span across multiple studies, programs, or even therapeutic areas. I like to share lessons learned, and assess the trends and effectiveness checks to see if what we have implemented has worked.The more quality data we have access to, the more we can try to intervene early and/or prevent the same things from happening again.

GCP Inspection Readiness Event is occurring in Philadelphia December 5-7, 2022

Sheri Kuss, clinical quality group lead at Pfizer, discusses the new "culture of quality" in clinical trials.

“Culture of Quality” In Action

FDA’s Center for Biologics Evaluation and Research (CBER) is updating how it manages a growing volume of cell and gene therapy (CGT) development programs, seeking added resources and revisions in its oversight of these cutting-edge therapies. Most visible in the elevation of CBER’s Office of Tissues and Advanced Therapies (OTAT) into a new “super” Office of Therapeutic Products (OTP). The change aims to improve functional alignment, increase review capabilities, and add expertise on new CGTs by establishing multiple branches and divisions in the expanded regulatory unit, as announced in the Federal Register on Sept. 28.

Stated goals are to help CBER address the “substantial growth in innovative, novel products” that present new “scientific, medical, and regulatory challenges that require changes to its structure,” including strategies to advance the Regenerative Medicine Advanced Therapy (RMAT) program. The added resources are needed to oversee more than 2,000 development programs involving CGTs, many involving innovative testing and manufacturing processes. This soaring workload has overtaxed CBER staffers, resulting in serious difficulties in retaining and hiring capable scientists.

The structural changes at CBER reflect agreed-on plans to hire new staffers with funding from recently reauthorized user fee programs. The PDUFA VII commitment letter calls for an additional 132 new hires for CBER in this coming year and another 48 employees the following year, mostto support CGT reviews at OTP. The reorganization plan calls for OTP to have seven offices—for therapeutic products, clinical evaluation, review management, pharmacology/toxicology, and two for chemistry, manufacturing, and controls (CMC)—for gene therapy, cellular therapy, and human tissues. There will be 14 divisions and 32 branches within those offices, providing attractive supervisory opportunities for new and experienced staffers.

These changes come in the wake of FDA approval of two new gene therapies that have drawn wide attention for both their therapeutic potential and for million-dollar price tags. Bluebird Bio’s Zynteglo was approved by FDA in August for patients with beta thalassemia, an inherited blood disorder causing serious anemia. That was followed a few weeks later with approval of Bluebird’s Skysona to treat a rare neurological disorder afflicting young boys. Zynteglo carries a $2.8 million price tag, Skysona’s list price is $4 million, but both therapies are expected to target less than 1,500 patients, limiting the overall cost impact for the US healthcare system. A greater spending effect would come from FDA approval of a new treatment for sickle cell disease from Vertex Pharmaceuticals and CRISPR Therapeutics, which plan to begin a rolling review by FDA in the coming months. The important potential benefits of these treatments, along with concerns about their impact on healthcare spending and access, speaks to the need for a highly capable and sufficiently resourced FDA oversight program.

These developments also highlight the importance of sound testing and production methods for therapies made from living organisms, which are inherently variable and difficult to control and measure to assure product safety, identify, quality, purity, and strength. The surge in applications from a broad range of firms, moreover, has made it difficult for CBER staffers to schedule formal meetings with each sponsor seeking advice on how best to perform manufacturing and testing processes. And publishing new guidance on these changing and emerging issues also takes time and resources.

In response, FDA looks to engage a broad range of sponsors on topics related to product development through a series of virtual town hall meetings. The first was held Sept. 29 and addressed how manufacturers should describe and inform FDA about CMC in applications for gene therapies.

 Wilson Bryan, OTAT (now OTP) director, opened the session by describing plans for establishing OTP as a super office to increase review capabilities and enhance expertise on CGTs and set the stage for OTP branch chiefs to field a broad range of queries, ranging from basic CMC policies for various stages of development, to the scope of potency assays and impact of delivery devices on dose potency and quality.

CBER maps modernization plan to handle surge in research and applications. 

Applied Clinical Trials-11-01-2022