Moe Alsumidaie

Many biopharmaceutical companies have discussed how the pandemic has changed clinical trials. However, study sites have also implemented strategies to bring studies into a new realm. In this interview, Aasma Shaukat, MD, MPH, study co-lead, professor of medicine, and director of outcomes research for the Division of Gastroenterology and Hepatology at New York University Langone Health discusses the site perspective.

Moe Alsumidaie: As we come out of the pandemic, can you tell me about your clinical trial design changes over the past two years?

 The pandemic accelerated things we were already trying to do in clinical trial design, including more virtual enrollment, point-of-care enrollment, and ways to reach populations that traditionally don't come to the clinic. Over the past two years, we saw clinical trials pivot to a more virtual enrollment platform. Also, they became more creative in reaching potential participants through social media and engagement channels other than just traditional in-person visits. Here's what a typical example might look like: Say there's a clinical trial available. To find out about the clinical trial, the patient would have to have a visit with a provider like myself, and I would have to remember to discuss the study with the participant and see if they're agreeable. Then a coordinator would call them, and they would come in for a visit. At that point, the coordinator will obtain consent and all the other necessary paperwork. Then the patient would come in again for a blood draw or some other metrics, and they would undergo the procedure or the intervention. Then there would be several follow-up visits in person in the clinic or research space.

The pandemic upended that model. So, the first change was that instead of waiting for patients to come to us to be able to talk about potential studies, we are now reaching out to them. And we're doing that through social media, news outlets, and the internet. So, now, in the comfort of their home, patients can learn what studies they're potentially eligible for and sign up.

Second, consent and education about the study can now be done virtually. So, my coordinators, for instance, pivoted to a Zoom or a virtual enrollment or telephone enrollment visits. Finally, we send mobile phlebotomy to patients instead of them having to come to the clinic to get their blood drawn. We did this very successfully in a trial designed to validate a blood-based screening test that recently completed enrollment, called PREEMPT CRC, which is Freenome's prospective study to validate our blood test for CRC screening among average-risk adults. We sent mobile phlebotomists to participants' homes to draw blood or collect other measurements during enrollment. And all the follow-up was either through virtual visits or by telephone. So that completely changes the paradigm of how studies are done. And it allows us to include a population that otherwise we wouldn't be able to reach out to.

the New York Times that diversity is still

 a problem in clinical trials, especially post COVID. Can you tell me a bit about why as an industry, we still have a long way to go toward ensuring that there's sufficient diversity in clinical trials?

 That's one of the things that we as a research community still struggle with. There's a lack of diversity in clinical trials. If you think about the standard model of how clinical trials were done, individuals who had access to information about the clinical trials were either connected at large medical centers or through academic centers or perhaps lived nearby. These patients also had the means and the time to participate in these studies, which by those conditions excludes many individuals. When Freenome designed PREEMPT CRC, we wanted to ensure diverse representation and broad reach, so we employed a novel hybrid strategy. First, what was important was going to smaller community networks and clinics. These could be in rural areas, or geographically dispersed locations, and they could also be areas far from academic or urban medical centers. Virtual enrollment allowed us to do that – we have participants from every ZIP code in the continental United States. Second, by using social media, we could reach participants and potential individuals that we otherwise wouldn't necessarily see in a clinic or perhaps in a clinic connected to clinical trials.

The third strategy was to go to practices and places where we know there are a lot of diverse individuals, such as urban neighborhoods—inner-city Chicago and New York City, as well as Florida and Arizona for the older demographic age groups. That was partly strategic and partly a result of a more extensive reach out to these communities. But if you don't do some of those steps, say it's a cancer screening trial, for example, you're limited to relatively sizeable comprehensive cancer centers. And you can imagine that the demographic that goes to those cancer centers isn't representative of the rest of the country. So instead, our PREEMPT CRC trial locations include community hospitals, health systems, private clinics, tertiary centers, and teaching hospitals, allowing our study to represent all patient experiences better.

Alsumidaie: Which of these methods was the most effective way to enroll patients successfully?

 There were multiple strategies. One is connecting to smaller networks. We used some of our partners and other resources to figure out where these small practices are that see patients who traditionally don't get a chance, opportunity, or exposure to participate in clinical trials. Second, the ability to offer virtual enrollment helped people who lived further away from a medical center, like longer-distance, drive, and those who didn't have access to easy transportation. This allowed those populations, many of them rural, to participate. So I would say those two were the predominant models that helped achieve this diversity.

The marketing industry has gotten very smart about targeting the demographic that one's looking for. And indeed, receiving an invitation is a good way for people to be exposed to the opportunity as long as it's up to them whether they choose to follow up on it and take up on the offer. So I see that proliferating and increasing with time. And in some ways, that does allow us access to individuals where we could even go a step further, who aren't even plugged into health care who perhaps are a younger demographic—a healthy forty-year-old—and they don't even regularly see a provider.

Alsumidaie: In general, people of color tend to be hesitant and distrust the biopharmaceutical industry and clinical trials, and they won't participate in those trials. Do you agree with this statement?

 Traditionally, patients of color do not trust clinical trials. I would say in this study; we found evidence to the contrary. Sites with many patients of color or a sizeable low-income population enrolled more patients than other sites. It depends on the type of study offered if it's a trusted provider, something individuals are enthusiastic about supporting and if it contributes to overall health. Early data indicates that the PREEMPT CRC study populations include approximately 11.3% Black and 10.3% Hispanic. The study showed us that reaching these populations can be done well.

Alsumidaie: Did the healthcare provider, the environment, and the trust between the patient and the healthcare provider make the most significant difference?

 It was both the healthcare provider and the study itself. The messaging is extremely important, how providers think the study will contribute to their health and the health of their peers. And how education is put in that messaging regarding what we're asking them to do. Certainly, answering some questions about your demographics and contributing by giving, allowing a blood draw before a scheduled colonoscopy already seemed to resonate with people as a good thing they wanted to participate in.

Alsumidaie: If you had one message or advice for people designing clinical trials and seeking to recruit diverse participants, what would that be?

 I would say, think out of the box—don't wait for patients to come and sign up for the study; think of innovative and creative ways to reach out and recruit the kinds of patients you hope that the drug or the study would help them.

Alsumidaie: Anything else concerning protocol design for enrolling a more diverse patient population? Specifically, what made this trial design so acceptable to diversity?

 I think it is part of the study in question. First, colon cancer screening is on everybody's radar because it is a significant health issue and a public health issue in the U.S. Second, the screening age was recently lowered to 45. So, that brings in a whole new demographic that we weren't screening before that is probably very curious and engaged in figuring out what is best for their health. And third, I would say multiple avenues and partners. It can't just be one clinic relying on its support network. Still, we expanded our network very widely—some through word of mouth, some through CROs, and others through networks of primary care clinics. So, be as inclusive as possible in bringing in some kinds of patient populations that would be important for this study.

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Aasma Shaukat, MD, MPH, study co-lead, professor of medicine, and director of outcomes research for the Division of Gastroenterology and Hepatology at New York University Langone Health discusses how sites have evolved since COVID-19.

How Study Sites Experienced Clinical Trial Changes During Pandemic

Protocols are becoming more stringent and tougher to enroll, and the biopharmaceutical industry faces the need to expand its patient access and diversity globally. Additionally, with the backdrop of global instability, the industry is also shifting its global strategies to mitigate risks should instability continue to increase. In this interview, Melika Davis, SVP of Global Clinical Operations at BeiGene, will discuss her perspectives.

BeiGene has spoken about the need to expand the clinical trial ecosystem and bring more patients into that system. Can you explain what you and BeiGene are doing to add more trial sites to that ecosystem and why this is so important?

: Expanding the clinical trial ecosystem means more options for underserved patients. The major clinical trials have historically been run in the G7 countries—and ours have as well—but we also realized that we needed to expand our trials beyond our start. We recognized the opportunity at BeiGene to place clinical trials in China because a significant, underserved population was there. About a quarter of the world’s cancer cases are in China, but over the years, and specifically in the last four to five years, we have grown tremendously beyond China to serve additional populations—which is critically important for patients. We are now running multi-regional clinical trials around the world. Now we're looking at South Korea, Latin America, and beyond the main G7 countries in Europe. But we have to be careful—we're a small biotech. We're not a big pharma company. We're trying to be as strategic as possible in where we need to go. Our expansion plan is in its infancy, but we've made tremendous progress.

What are you doing to plan for global instability risks and wars?

: We quickly put a business continuity plan together because of COVID. When COVID first started occurring, we didn't know what to expect. I think we are well prepared to handle global instability—but wars are complicated. First and foremost, we are humanitarian. The first thing that I always think about is the patients. No matter who they are, they are global citizens. How do we make sure that they get their study drug? That is of the most importance. It's challenging to do this in a time of war, but we're working with and hearing what the regulators are saying and looking at NGOs and other organizations to assess their plans. We're also trying to build bonds with them to ensure that we don't disrupt the supply chain.

It isn't easy to do. We're open to different solutions and trying to be as creative as possible without violating any regulations or any sanctions that may be happening. We have to be mindful of that, too.

You've talked about expanding your study system geographically, and you've looked to expand your trials outside of the largest cancer sites. What are you and your team doing to bring the physician and patient communities together into your building ecosystem?

: We're approaching this on two fronts. One front is the data. We strongly believe that the data needs to be globally available. That is important because as we generate our data, we should share that data regularly and as soon as possible. We are following, of course, all of the practices and the ethics and compliance regulations, the data transparency and disclosure guidelines. But it's also essential to get this information out to the scientific community as quickly as possible. The sooner we share this information, the sooner the community can develop an evidence-based understanding of our treatments.

The other front is operations. From an operational perspective, we always look at how we can make sure that patients know that clinical trials are available to them. It's the same thing for the community physicians. Are they interested in participating in a clinical trial? If so, we would work with them and look to make this participation a lot less burdensome. We recently talked about potentially creating a forum of community physicians, nurses, those taking care of patients, patients themselves, and patient advocacy to speak to us about our clinical trials. How can we improve them? What are their thoughts? Really considering that in the future.

We're also looking at the technologies we can use to make patient participation easier, for example, electronic informed consent and wearables. Also, how can we ensure that patients can go to sites close to their community and do lab tests, for example? I think COVID has taught us that it can be done.

Decentralization is a topic on everyone's minds now, and everyone's talking about it at medical meetings. Do you think that decentralized clinical trial approaches are here to stay? Or do you think it's a fad?

: I think they are here to stay. It's been, what now? More than ten years that we've been talking about decentralized trials? I hope that they will continue because the future is utilizing technology as much as we can and being as transparent and collaborative as we can. I'm talking about biotech companies, pharma companies, research institutions, and regulators. If we want to beat cancer, that's what we should be doing.

What are your thoughts on the patient diversity movement?

: As part of our mission, patient diversity, equity and inclusion is key. We want to make sure that we have diverse patients with diverse backgrounds. The FDA's recent 2020 guidance was beneficial. We set up a task force and created a cross-functional BeiGene clinical trial diversity initiative. We set our objectives to build on the existing efforts that we had done. We've also established a BeiGene Clinical Trial Diversity Institute, which is geared towards training clinicians and making sure that we understand where underserved patients are and which support staff are helping these patients. We need to understand the landscape. We also have patient education and advocacy efforts.

I think it does not just work that we as an industry have to do, but also the research centers. We're looking at a lot of ideas. First, going into community centers will help. We can do some good work there to ensure a diverse population of patients and facilitate community-engaged clinical development. We are starting to implement these initiatives. I'll add that we are very particular when we do our study feasibility to understand where diverse patients are, and then make sure we include community centers into our line of sight.

Hopefully, all of that and the other actions we are taking should help us have a more representative patient population in clinical trials.

Excellent. Why is BeiGene predominately CRO-free? Since you're expanding into different regions of the world and need to build clinical trial infrastructures, how is BeiGene establishing these infrastructures in other countries, and why not use CROs? Why have you vertically integrated all your operations internally?

: I like how you say it. It is vertically integrated. Although it's vertical, it's also horizontal...we built an internal capability in our clinical development team, specifically in clinical operations. We believe that by having an internal team, we will allow for more flexibility, which will allow for faster decision making and better clinical site relationships, which I think is important. In addition, by doing all of this, we will be more cost-efficient. Before 2018, 100% of our trials were handled through CROs. Looking at our portfolio today, more than 90% of our trials are handled internally.

In four years, we are seeing that we're able to start our clinical trials a lot faster. We joke with our team that the speed at which we go is fast, and what takes weeks or takes months for a CRO to do with starting trials, it takes us days or weeks to get it done. That disrupts the standards by creating new ones, which we're very proud of. It speaks towards the relationship that we have with our clinical sites. I think that's incredibly important. You cannot do that through third parties. You have to do it in-house.

Melika Davis, SVP of Global Clinical Operations at BeiGene, discusses her perspectives on patient access, diversity, and risk mitigation.

A Changing World Demands Changing Biopharmaceutical Strategies

SCOPE 2022 was packed with many topics ranging from clinical biomarkers, outsourcing, enrollment, and protocol development, to name a few. However, in particular, three topics stood out to me as relevant and breakthrough; these topics included clinical data strategy and analytics, wearables and digital biomarkers, and risk-based quality management. I will summarize notable takeaways from these topics in this article.

eClinical analytics and predictive modeling

There was much talk around eClinical analytics and predictive modeling. Jennifer Price, Executive Director of Data and Analytics at THREAD Research, showcased some of the first predictive models and visualizations ever introduced to the clinical trials industry using data from a decentralized clinical trial setting. For instance, analytics, such as study tasks and training, are used to predict patient dropout rates, and evaluating compliance with study procedures helps predict patients at risk of non-compliance. Knowing this information helps study staff identify and conduct early engagement activities to change the future course of the study positively. "Using predictive models to predict out study visits, compliance and completion are key to study success," said Price.

Artificial intelligence (AI), machine learning (ML), and natural language processing (NLP) approaches were featured by Xiaoying Wu, Vice President, Data Science Platforms & Privacy, Data Science at Janssen. Wu presented a case study on Janssen's COVID trial; Janssen developed a disease forecasting model that leveraged machine learning and real-world evidence data to forecast COVID hotspots with a 90% accuracy rate, which helped reduce the study's duration by 6-8 weeks. To do this, Janssen took a scalable approach by building a system that allowed access to data scientists and quantitative clinicians to conduct analyses and share the analyses across the organization. "It is important to monitor and analyze the model's performance and feed that back into the machine learning models to continue to improve the predictions," said Wu.

Digital endpoints was also a topic at SCOPE. While there was much discussion on the subject, a presentation by Carrie Northcott, Director and Project Lead at Pfizer, was interesting, as she discussed studies that compared the validation and accuracy of novel digital endpoints against traditional endpoints at the site. By using digital endpoints, researchers can obtain a better picture of patient outcomes through high-frequency data collection that provides more comprehensive information about patients. "Going for a study visit, you may not get the full picture; you're getting points in time evaluation, so by using digital health technologies, we can now get a real picture of efficacy and safety of our drugs, and we get quantitative measurements," said Northcott. To elaborate, Pfizer conducted a study that evaluated patient gait in the clinic on a gait mat versus lumbar sensors the patients took with them at home, and the study's endpoint was to assess gait speeds between a variety of age ranges. Pfizer discovered a clinic bias that occurred; in the clinic, older and younger patients tended to have similar gait speeds; however, when patients were sent home with the lumbar sensor, the older group exhibited lower gate speeds compared to the younger group. Essentially, older patients walked faster in the clinic setting than in their everyday environments.

Several experts, including FDA, discussed the ICH-E8-R1 draft and updated views on clinical trial quality. The definition of quality seems to be moving away from perfection and more towards a quality culture within the organization. This stems from both profound experiences with quality and the intent to design reproducible processes and results and starts with collecting data and drilling down to identifying root causes. "There needs to be an open dialogue on quality issues (within the organization); how can you learn if you shut off (communications on quality events and resolution) and keep them in the quality management group?" said Andy Lawton, Director and Consultant at Risk Based Approach, Ltd.

David Burrow, Director Office of Scientific Investigations at FDA CDER, also discussed quality expectations. Burrow discussed that clinical quality involves four facets. The first includes the scientific question; whether high-quality evidence will inform decision-making through the use of a preventative, diagnostic or therapeutic intervention. Second, whether the trial design is adequate to answer the scientific question. Third, whether the data produced are sufficiently accurate and reliable. Last, ensuring that patients' safety, rights, and welfare are protected. Burrow said, "quality in clinical research is how we ensure the data supporting drug approvals are reliable and interpretable in support of the indication in the labeling." Burrow also discussed several critical risk assessment and management methodologies to form an ecosystem, including risk identification, risk impact assessment, risk prioritization and analysis, and risk mitigation planning, implementation, and monitoring. Burrow described this process as an ecosystem that goes beyond a trial and applies to the organization. "We're talking about the ecosystem as a whole, organization as a whole, the structure, the technology, the data systems, the portfolio of products that you have across the organization and all of the other vendors and contractors that are involved… but what's fundamental to clinical trial quality is people; the people who are critical in making sure that the trials work," said Burrow.

In summary, we are seeing tremendous advances in data analytics and predictive modeling in clinical trials, especially with decentralized clinical trial technologies, new studies are proving that digital biomarkers can be superior to traditional data collection methods and will likely become an expectation for collecting data in many trials, and the risk and quality management perspectives continue to shift, with them moving out of a singular function within the clinical quality department to a holistic, cultural and organizational level.

Clinical data strategy and analytics, wearables and digital biomarkers, and risk-based quality management highlight notable takeaways.

Notable Takeaways From SCOPE 2022

In 2016, there was much buzz around the talent gap impacting entry-level clinical research positions within the biopharmaceutical industry. 

ACRP's position paper on the clinical research associate (CRA) shortage

 and ACRP helping to address the gap with its Joint Task Force for Clinical Trial Competencies raised awareness around the problem. ACRP's position paper also highlighted the industry's expectation of a two-year minimum experience requirement for entry-level CRA positions. Still, to this day, word on the street is that the shortage remains as CRA demand increases, and entry-level talent remains low. This article will evaluate why the shortage still exists and explore options that could address the shortage.

Why is There an Entry-Level CRA Shortage?

After researching the literature and conducting data analyses, I’ve discovered four main themes contributing towards the entry-level CRA shortage:


Many Sponsors Require CRAs to Have a Minimum of Two-Years' Experience

 - It is no secret that the industry has gone by a two-year minimum experience standard to place CRAs on their trials. One would think CRAs would be young and enthusiastic professionals and go straight into research jobs, but the 

10% being 20-30 years old, 27% being 30-40 years old, and 63% being over 40

. This may be the case because clinical research is not a well-evangelized career path out of college. Many professionals zig-zag through different life sciences careers before becoming aware of a career in clinical research, landing a clinical research job, and gaining the experience necessary to become a CRA. This is also especially tough on CROs because sponsors do not want inexperienced CRAs to work on their trials, 

resulting in CROs allocating too many trials and more complex studies to their already strained workforces and causing CRA burnout

. Another possibility for this age trend is the data source, as the reference data may include roles for both junior and senior CRAs, with the majority of CRAs falling in the senior level (from having years of experience).



High Turnover: CRAs Move on to Other Roles or More Senior Roles – 

The average total turnover rate for CRAs is roughly 20%, and 48% of CRAs stay in their positions for 1-2 years before changing jobs. Many CRAs start at CROs, and those positions are especially prone to high turnover – primarily due to salary expectations, as compensation levels remained the same for the past decade and CRAs switch companies to attain higher salaries. Additionally, some CRAs do not have a clear career path within their organizations, leading to them leaving their positions for more senior roles elsewhere, and do not feel appreciated in their existing roles.



Growing CRA Jobs and Low Unemployment Rates- 

It is no surprise that since CRAs are in such high demand, they are almost always employed; in 2019, the CRA unemployment rate was 

, the compounded annual growth rate (CAGR) for CRA jobs from 2016-2019 is 5.3%.



Clinical trials and eClinical technology systems are putting more strain on CRAs, as 

today’s studies are becoming much more complex

, and the sheer number of clinical trials is increasing (

), also contributing to increasing CRA resource strain and burnout in the existing workforce.

This evidence draws my perspective to the factors causing the entry-level CRA shortage: CRA entry barriers and CRA siphoning. 

 demonstrates the CRA shortage problem; increasing job postings coupled with the two-year minimum experience requirement barrier prevents those jobs from being filled, and other CRA job postings and senior clinical research job postings requiring experienced CRAs are siphoning CRAs from entry-level positions. The combination of CRA entry barriers and the siphoning of CRAs to other roles coupled with entry-level CRA job growth are creating the entry-level CRA shortage.

Why the Two-Year Minimum Experience Barrier?

The industry follows ICH-E6-R2 guidelines when it comes to clinical trial professional expectations. It is important to note that the ICH-E6-R2 does not define how many years of experience are required or what CRA experience is; the industry has evolved to a two-year minimum experience preference. ICH-E6-R2 

repeatedly mentions that personnel "should be qualified by education, training and experience.”

All CRAs must train and have an education, which is accessible; however, is ‘experience’ also a proper guide to performance? I believe sponsors may equate CRA experience with performance and quality; however, data shows that CRA experience is not related to CRA performance and quality. I recall conducting a data analysis 

showing a minimal difference in quantified CRA performance, regardless of CRA seniority and years of experience

. The analysis also revealed that CRAs’ most competent skills involved critical clinical trial competencies, such as protocol requirements, informed consent, and delegation of authority. Other skill areas where CRAs lacked involve competencies that can now be tracked and caught by quality management and technology systems, such as IRB reporting (via CTMSs) and potential fraud (via statistical RBM). One of the most critical skills CRAs lack involves source documentation, which, in my experience, requires more expertise and thought process than experience; despite my opinion, the data shows all CRAs demonstrated lower competencies in that area, regardless of seniority and experience levels.

Figure 2: Average Domain Scores by CRA Title (N= 429 with Confidence Intervals)

CRAs are trained to monitor clinical trials using consistent methodologies during CRO bootcamps. While unique perspectives gained from experience can add value (especially in a managerial role), the analysis mentioned above clearly shows that in a CRA role, experience makes a minimal difference in performance when assessed in a standardized environment, which seems to correlate with industry thought leader opinions that 

two years of CRA experience is not equivalent to CRA performance

. Additionally, while there is some consistency with training programs, the CRA shortage issue continues to balloon, indicating that existing programs and methodologies are not addressing the root cause of the shortage, which is to fulfill the ‘experience’ requirement.

Can CRA Training Programs Include Required “Experience?”

Most clinical research professionals know the CRA boot camps at large CROs, which provide the training competency required by ICH-E6-R2 and offer some form of standardization to become a CRA. However, few sponsors will allow the placement of an inexperienced CRA on their trial unless they have two years of experience. While ICH-E6-R2 mentions the experience requirement, can’t newcomers to the industry who have educational and training requirements also undergo an experiential process? Many professions incorporate experience in their training programs; physicians go through fellowships and residencies, pharmacists go through rounds, medical assistants go through internships. Why can’t entry-level CRAs also have an experiential aspect to their training acceptable to sponsors as an industry standard?

Some training enterprises are turning this gap into an opportunity. For example, 

, a startup company, is attempting to address this gap by raising awareness about the clinical trial profession to students nearing college graduation at universities,and administering gold-standard CRA training to recent graduates. Virb has gone further by employing a CRA performance oversight program after the CRA has been hired. “We are embedding an experiential core into our training using advanced ed tech to simulate real-world experience, real-time coaching, mentoring, and experts-on-call to overcome the lack of years in the role,” says Garrett Walker, CEO of Virb.Moreover, non-profits, such as ACRP, 

launched a variety of programs and taskforces

 to define CRA training requirements for the industry to follow, though the performance and impact of these programs on the CRA shortage is unknown.

What Will It Take to Change the Two-Year Minimum Experience Requirement?

While many factors identified in this article are contributing to the CRA shortage, addressing the two-year minimum experience requirement will bring significant relief to the problem. Perhaps it would take newly issued guidance from ICH-E6-R2 to clarify their definition of ‘experience,’ or maybe they kept the definition vague for a reason and will maintain its position. Either way, the industry-wide CRA shortage is self-inflicted because of an arbitrary number of ‘years of experience’ that has descended through the years by the industry as a ‘standard,’ because ‘we’ve always done it that way.’

COVID caused a significant shift in the industry's clinical operational methods and broke through ossified conceptions of how trials should be run by decentralizing them; however, COVID was a crisis that demanded immediate action. While the CRA shortage may feel benign at the moment, it will snowball into a crisis if the industry does nothing to change the CRA entry barriers. Let’s face it; the issue was discussed in detail in 2016, yet, the problem persists. Perhaps in the future, the CRA shortage will become so painful to the industry that there will be no choice but to accept novel approaches to remove the entry barriers to meet ‘training, education and experience’ requirements and fill the shortage. However, it would take a culture shift and some giants, such as big CROs, to remove this roadblock since they have the capital and credibility to change industry perceptions. For certain, whichever CRO figures out this problem first will realize significant benefits, such as added revenue (due to increased capacity), advancing more studies, and moving to become the leading brand in the industry.

Moe Alsumidaie has received funding from Virb to write this article.

In this article and video, Applied Clinical Trials blogger and Head of Research for CliniBiz Moe Alsumidaie, MBA, MSF, takes a deep dive into the reasons behind the CRA shortage and how industry can proactively address this problems. 

Entry-Level CRA Shortage Still Crippling Clinical Trials

Asia’s biopharmaceutical enterprises are seeing massive market penetration opportunities in the West. Their ability to conduct early-phase trials in Asia at a lower cost and then obtain funding to run later-phase trials in the US puts them at an advantage. As a result, they can enter the Western marketplace with lower-priced medical products. In this interview, Dr. Harish Dave, CEO of Singapore-based AUM Biosciences, discusses evolving strategies for Asian biopharmaceutical enterprises.

Moe Alsumidaie: What is AUM’s vision of bringing affordable cancer treatments and more agility in clinical trials and go-to-market strategy?

 The traditional arena for clinical research has been the US, Western Europe, Japan, and other “westernized” countries based on the robust regulatory framework, capable investigators, and strong research facilities. As the number of clinical trials has increased over time, so has the cost of clinical research. The number of patients willing to participate in clinical research has remained flat or even declined, hampering recruitment and timely study completion. Additionally, facilities and researchers are at a saturation point resulting in further delays.

We have seen several countries in the Indo-Pac region develop a more robust health care and research infrastructure, with highly regarded investigators at the helm of affairs. Patients in these regions are more willing to participate in clinical research, while the population size enables speedy recruitment. Labor and cost arbitrage between regions means we can conduct world-class research cheaper and faster than is possible in the US and EU. The critical element, of course, is that there can be no compromise on trial design, execution and data collection to deliver a robust drug development package. These advantages can be used to carry out Phase I rapidly and, to an extent Phase II studies before incorporating US and EU sites into global Phase II and III designs.

This approach led to the rapid conduct of Phase II and II oncology trials at premier centers and at a global standard before involving many sites and countries, including the US and EU. The time savings results in a longer market time before patent expiration, and there is also the direct cost savings from labor and cost arbitrage.

AUM’s executives are an experienced and diverse group of individuals who have spent time in almost every major region of the world and have the experience and knowledge to use the Indo-Pacific region to accelerate drug development. This translates directly into going to market strategies that do not rely on extracting the maximum price the market will bear but, instead, on a realistic price. More patients stand to benefit from this affordable drug development strategy. AUM hopes to do its part in reducing health care inequities that continue to plague the modern world.

The traditional flow of drugs from the West to the East brings “western costs.” AUM’s strategy is to reverse this flow and go from Asia to the West, satisfying the need of the Asian population for innovative and affordable drug development and reducing the cost of health care in Western countries by introducing drugs at an “Asian” price point.

MA: What challenges have you faced in your Oncology trials?

In a sense, this is not dissimilar to other areas of clinical research but is perhaps more of an issue in oncology. The advances of the last 2-3 decades have resulted in a great deal of segmentation within oncology diseases. Many of our newer therapies address small subsets of patients with inclusion criteria requiring documentation of a particular mutation or biomarker and, sometimes, exclusion of other mutations or biomarkers. This segmentation means we are looking to identify relatively rare subsets for study entry which slows the recruitment process. A classic example is Phase I oncology work. The traditional 3+3 design recruiting “all-comers” with solid tumors can quickly recruit. But if only certain tumor types or certain biomarkers are required, that can greatly slow down fulfilling recruitment goals for each dose cohort.

The second issue is compliance, especially as we move to oral therapies self-administered by patients. Even with a potentially terminal diagnosis, patients may not take their medication on time, or in a fasted or fed state as required, or forget to take medicine altogether. As a general rule, the longer someone is on therapy and the greater the adverse events (AEs), the lower the compliance. This leads to gaps in data and impact outcomes, necessitating a larger trial size to overcome this obstacle. Paradoxically, having a good response may also lead the patient to become non-compliant.

Study retention also can be difficult in a cancer population. Many patients are already debilitated from their underlying disease. Adding to that, AEs of our medications, frequent clinic visits, blood draws, imaging, and other invasive procedures make retention challenging.

The COVID pandemic has also resulted in additional challenges–our patients are reluctant to venture out and risk infection in their immunocompromised state. Many clinics and hospitals are not allowing caregivers to enter the facility to minimize the risk of contagion. And several doctors stopped seeing patients or relied heavily on telemedicine which may not be entirely satisfactory to the patient. From the investigator and pharma perspective, clinic visits were disrupted with missing data and delayed imaging, and Clinical Research Associate’s (CRA) inability to get on site (though this has been mitigated by remote access to Electronic Medical Record (EMR) EMRs). As the omicron variant has demonstrated, we will continue to see newer and potentially more infectious variants emerging, making it difficult to go to the status quo.

MA: How is the pandemic posing challenges for your clinical trials?

 AUM Biosciences were fortunate that our Phase I study had completed recruitment just before the pandemic started. However, the dislocation in services from widespread lockdowns resulted in significant delays in data collection and management of research samples. Critical plasma and serum samples were left to languish at research sites for many months with potential degradation of analytes and loss of valuable clinical research information. Even when we could transfer them to appropriate laboratories for analysis, the staff shortages, backlog of samples, and supply chain disruption of critical reagents and parts caused troubling delays in obtaining and analyzing data. From discussions with other, similarly situated biotechs, we know that recruitment on studies ground to a halt and has only barely started to recover. Investment capital dried up rapidly–many investors became gun-shy and preferred to hold on to dry powder rather than invest when the level of uncertainty was high. And what investment dollars remained made a beeline to COVID-related research and mitigation strategies. This was particularly punishing for small biotechs heavily dependent on ongoing capital raises to fund their research burn.

This was a tremendous learning experience for many of us. It showed how critical the global supply chain was for clinical trials, not just for large companies and medium to heavy industries. Established vendor relationships were crucial to helping many of us weather the cash crunch we faced–their tolerance and willingness to extend credit and offer favorable payment terms helped many biotechs stay afloat. The lesson that cash is king was driven home by the shortage of investment capital during much of the pandemic. It served to emphasize the importance of securing enough financing, including debt financing, to survive such a significant global dislocation.

We, at AUM, were undoubtedly fortunate in that regard. As a company built by industry veterans in the clinical trials space, our extensive and deep connection with contract research organizations (CROs) and other vendors at their highest levels allowed us to secure favorable terms when money was hard to find. Despite omicron, there is a sense that we are emerging from this crisis and, to an extent, have learned to live with it allowing business to go on and research to go forward.

MA: Out of all the small-molecule drugs developed by AUM Biosciences, can you cite a case study wherein AUM Biosciences managed to overcome challenges in a unique way?

 AUM has a portfolio approach to drug development and has worked hard to build out a pipeline of drugs at various stages of development, from pre-clinical to Phase I (and now Phase II). While all aspects of business activity slowed down and clinical research almost ground to a halt, we were able to reprioritize our work by shifting the focus to earlier stage drugs and testing in cell culture and animal models instead of human subjects. This allowed AUM to retain staff (and even grow) during the pandemic and progress the portfolio to a point where we could rapidly go back to the clinic once the research facilities opened up for business. Such risk mitigation would not have been possible with a single molecule company–not only would that have delayed us significantly, but it likely would have necessitated a reduction in force. Once disrupted, carefully assembled teams can be hard to put together again and lead to the impaired outcome for many months or years after the event.

Most small companies in our space are far too busy managing their day-to-day activities to pay attention to global risk management. However, COVID has taught us that proactive global risk management is critical, perhaps even more so for small than large businesses. The C-suite must contemplate black swan events and strategies to mitigate against them.

MA: Tell us more about your clinical trial pipeline and if you have any specific strategies to ensure success in times of a pandemic that has impacted investments, focus as well as the speed of clinical trials.

 AUM has two advanced candidates entering Phase II trials and additional candidates in late pre-clinical, all backed by an AI-driven drug discovery platform and a biologics platform. Our approach is to drug the undruggable and avoid or overcome resistance through combination therapy approaches. Drugs in our portfolio are selected for their activity against a single cancer type and, ideally, multiple cancer types, thereby giving us various shots on goal. A consequence of this “one drug many targets” approach is the scalability of our research enterprise. This is amply demonstrated with the AUM001 MNK inhibitor. This selective translation inhibitor has activity in several solid tumors, which allows us to scale our research effort to explore one or multiple tumor types as determined by the availability of capital and availability of clinic resources during the COVID pandemic. Newer trial designs like basket trials allow us to efficiently explore multiple disease targets cost-effectively, channeling investment into the successful arms and pruning the unsuccessful arms. Using Indo-Pac countries as our home ground advantage, we can execute our studies more rapidly than many of our West-focused counterparts. Speed is of the essence in drug development as the patent clock is ticking–every week saved in development is an additional week of patent-protected marketing of the drug.

, MBA, MSF, is a thought leader and expert in the application of business analytics toward clinical trials, and Editorial Advisory Board member for and regular contributor to Applied Clinical Trials

Dr. Harish Dave, CEO of Singapore-based AUM Biosciences, discusses evolving strategies for Asian biopharmaceutical enterprises.

Asian Biotech Clinical Trial Demand Moves to the West

Decentralized Clinical Trials (DCTs) have evolved from concepts into a much more structured approach within the biopharmaceutical industry. The concept has become so significant that collaborations, such as Decentralized Trials and Research Alliance (DTRA), have emerged with strong support from industry leaders to help provide guidance and clarity around DCTs and industry best practices. In this interview, Craig Lipset, Co-Chair of DTRA, will discuss the evolving nature of DCTs and DTRA’s initiatives.

Moe Alsumidaie: What prompted you to found DTRA?

 The genesis for DTRA dates back before the pandemic. At that time we had many conference panels related to decentralized clinical trials where leaders were coming together, sharing some fabulous ideas and opportunities, but then would all head back to their day jobs and leave all those opportunities on the table until we came back together at the next conference to pick up those conversations. DTRA Co-chair Amir Kalali and I believed there was need for a space for those conversations to develop and ultimately create solutions together, which gave rise to DTRA.

MA: Are DCTs clearly defined, or are we in the beginning phases of defining DCTs?

 When you look at existing initiatives like the Clinical Trials Transformation Initiative and IMI Trials@Home, you start to see some consistent themes for DCT definitions. These definitions tend to include the use of technology and/or innovative processes that enable visits outside of a conventional research site. So, this is about technology such as those that can allow self-reporting of data, sensor-derived data, the use of video, and so on. And it's also about process changes, such as the use of home health and visiting nurses, acquiring labs locally, drug distribution to the patient's home, the possibility of administering medicine in the patient's home, or even configuring centralized or “meta” sites. It's not just a tech play; It can also be a heavy process play, and the desired state is to create options for people in how they engage, not necessarily forcing everything in the home because that's not right for every patient.

You tend to see many of those words resonating in terms of how people define this. But when a study team goes into Google and searches for a decentralized trial provider, it still turns into chaos. You wind up with a list of very different solution providers, which becomes extremely hard for study teams to navigate. Who is doing what? What collection of solution providers do I need to support my study today? Many of the large pharma have gone from late last year relying almost exclusively on their CROs to serve as their general contractor and navigate various solutions, to now having sponsors navigating that space and selecting specific partners for different DCT-related capabilities. I think for a lot of small and midsized pharmas, though, it's still a very confusing ecosystem to have to navigate.

 I think this is an exciting time for decentralized research, but it is a crucial time for us to leverage organizational momentum and enthusiasm to create sustaining commitments in these areas, making sure that our organizations are ready to continue to adopt at scale and ensuring we're learning from the experiences that are going on today to help to optimize our processes in the future. Solutions close to the center of the decentralized universe include many that sponsors have been doing for years: ePRO and eCOA. Many have already been doing visiting nurse and home health. Decentralized builds and expands on these competencies. So, organizations don't have to look at this as foreign and intimidating. Incremental counts and every step forward is an important step.

And so, where decentralized is now increasingly accepted as a competency, what innovations continue to grow and expand this core? It's an exciting time in that there is an established ecosystem of solution providers today, but that ecosystem continues to grow with new and creative innovators coming up with novel approaches to wrap around today’s DCT environment. And that's been very exciting to see, and I encourage folks out there to treat this as an opportunity for incremental expansion.

MA: What methodology is recommended to build a DCT infrastructure?

 What you see today are sponsors that have gone through a disciplined process of looking internally at their portfolio and future study needs. Based on those portfolio needs, they are then identifying which decentralized research methods their study teams will need to be able to access, finding new partners if they don't exist in their network, reviewing SOPs and training to make sure that those solutions can fit in their operating environment, reviewing protocol templates and other tools, and making sure that culture-wise the organization is ready to engage. The next step is then to be able to pair each study with the right decentralized research methods.

Some people may say, "we should use a clinical decision support tool.” Ideally a team should be able to input their protocol and have a data-driven process to find the right decentralized tools to make a successful study. Unfortunately, we don't have the body of data and evidence yet to power that. Until that body of data grows we have human processes that look at regulatory intelligence based on the countries in which you're operating, the safety profile of the investigational product and how it's administered, patient input and insights, and a host of other factors to try to infer which solutions are suitable for which study. Some large pharmas have put in place internal subject matter expert-driven teams to help advise study teams on this. More often than not, the rate limiter for those solutions is driven by cultural constraints within the organization. Cultural aspects include whether teams are supported, or do they feel constrained in how much they can do? How much change could they embed at one time? That tends to be the process today, and that works well for large pharma, but it still is hard for small and some mid-sized pharmas, who need to rely much more heavily on their CROs and other partners to help them navigate that landscape and make good decisions on which solutions to include.

 Once upon a time, a lot of the jargon people were hearing was that studies would evolve from brick and mortar to a hybrid middle state to some desired future state of being fully remote and fully decentralized. And in many ways, that's the technologist's view of the world. However, the reality is that when you talk to patients and research participants the sentiment about a research site is exceptionally high. The average site rating on TrialJourney is 4.4 out of five. When we look at data from CISCRP, perception of their experience at sites is overwhelmingly favorable. The challenge in clinical research studies is not that patients don't like their sites; it’s that they can't always get there. And so when we focus on access as being the challenge, we tend to land more often than not on hybrid studies, not as being a fuzzy middle ground, but being the desired end state for many studies.

Today’s desired future state for many is to enable participants to have more choice and flexibility on a visit-by-visit basis, powered by endpoints and measurement approaches that capture high quality data agnostic to location., In this desired future if a patient wants to go to a site, we do not deny that to anybody, but if they can't, we have other options available based on their individual needs. So, given that future state, sites will continue to play an essential role in research conduct and participant experience. Organizations like SCRS were also very thoughtful in ensuring that the sites had a clear role to play and a pathway for them to start engaging with the use of video to support patient visits, even before the pandemic.

The ability for different types of sites to invest in training and tools to support decentralized trials will vary greatly. We may start seeing separation among different in terms of their ability to invest in the state of readiness for DCTs. I suspect that more and more sites, especially more extensive networks, will take greater ownership over many of the tools and approaches in DCT. For example, will some site networks or academic-based sites make home visits for their partiicpants an internal capability? Can sites invest in their own DCT-supporting technology, such as eConsent or video visits? And can sponsors focus less on pushing less unfamiliar study-specific technology to the site, and instead start to focus on minimum quality standards and interoperability? As we see more of that, it may create some differences among different profiles of sites and how much they're able to do there. As these opportunities emerge, we will need to make sure all sites can be supported so that those unable to invest are not left behind.

MA: What are DTRA’s priority initiatives?

 DTRA is a member organization. One of our first tasks in bringing these leaders together was to define a discreet set of priorities for the organization, and our members defined four. The first is toward a clear set of definitions and language. The second is around best practices and our ability to learn from recent experiences. The third is education and using data and evidence to grow this community. And the fourth relates to those remaining barriers to global adoption and how we can start to address those together.

We then defined a collection of initiatives beneath each of those four priorities. And today, there are 12 initiatives across these four priorities supported by DTRA members. For example, some initiatives create pathways for us to aggregate and share evidence of the impact of decentralizing and use that as a foundation for curricula and other types of education and training. TSome are creating platforms that allow us to track regulatory intelligence and additional insights globally to help study teams and operators understand the global landscape related to DCTs. We share details on all 12 initiatives and their progress at DTRA.org, and all of the work product is meant for the public domain to improve the global research environment. So, there's a wide range of initiatives right now that collectively are meant to ease the global implementation of DCTs for our community and the community at large.

, MBA, MSF, is a thought leader and expert in the application of business analytics toward clinical trials, and Editorial Advisory Board member for and regular contributor to Applied Clinical Trials.

Craig Lipset, Co-Chair of DTRA, discusses the evolving nature of decentralized clinical trials and DTRA’s initiatives.