Never before have operating conditions for clinical studies been more difficult. Clinical operations groups face growing pressure to get drugs to market faster while improving efficiencies and study quality. Development costs continue to rise. At the same time, the logistics of conducting a clinical trial have become more complex in the increasingly competitive and regulated environment.

As the operating environment has become more challenging, The CenterWatch Monthly asked four experienced, high-level clinical operations executives about the issues that keep them up at night. Some of the concerns were surprisingly mundane, while others got to the core of why they choose to work in the clinical research enterprise.

One theme that emerged was a growing concern about capacity and resource management, particularly in regard to sourcing global clinical studies. Another prominent issue involved the increasing use of technology and electronic systems, which has helped expedite study timelines but also has created new challenges. In addition, executives worry about the effectiveness of patient recruitment strategies and want better ways to reach potential study participants.

The responses offer examples of how some companies are changing practices to improve operational efficiencies and also suggest opportunities for stakeholders and service providers that want to better support clinical operations teams.

In this story, clinical operations heads from Biogen, Pfizer, Sunovion Pharmaceuticals and Merck talk about what keeps them up at night.

Establishing meaningful patient engagement

Clinical operations executives share day-to-day worries about delivering studies that meet study timelines, budgets, quality standards and compliance requirements. The responsibilities can be overwhelming. Yet for Murray Abramson, M.D., vice president of global clinical operations at Biogen, many deeper issues that are core to the success of the clinical research enterprise also occupy his thinking. Many of these concerns center on patients and sites.

“You always want the patient to get the very best. You always want them to get the best treatment, the best support and feel appreciated. Ultimately, it’s making sure that you have the best drugs for the patients who will benefit the most,” said Abramson, who has held leadership positions at both Biogen and Merck. “What really creates the biggest angst or concern has to do with the patient and the site.”

In particular, Abramson is troubled by questions about how to effectively engage patients in clinical trials who could most benefit from research. Given the current system of clinical operations—which is tied to conducting clinical trials at a diminishing number of experienced investigative sites—questions about how to identify and attract patients for clinical trials, and ways to help as many patients as possible, keep Abramson awake at night.

“The number of patients out there and available to go into trials is limited by the system we live in. It delays the development of the drug and ultimately it takes more time, money and resources. It increases the difficulty in bringing more compounds to the market,” he said. “There is not a shortage of patients with terrible diseases, such as Parkinson’s or Alzheimer’s; it’s the distribution of patients and how we connect with one another. The next great opportunity to transform our space is finding ways to make appropriate and effective connections to bring the right patients into studies and to provide them study drugs in a constructive, ethically appropriate and compliant way in order to get answers faster so we can bring wonderful, effective medications to market.”

Abramson added that from a quality standpoint, questions about the scientific integrity of protocols aren’t always on the forefront of operational concerns, but should be. Are the right scientific questions being asked? Will the answers help patients? If the study results are negative, does that mean the drug really doesn’t work, or could the findings instead reflect a bad protocol?

“When we create a protocol, regardless of its feasibility or its ability to enroll, will the study honestly and accurately answer the right scientific question? That is something that keeps me up at night. Companies invest hundreds of millions of dollars on clinical trials and part of their success, aside from getting it done, is whether you are asking the right question and if you have set up the sites and trained the monitors and personnel to answer the question properly,” he said.

When it comes to questions about budgets, Abramson said sponsor companies typically don’t have a good understanding of what it costs to operationalize a study using in-house resources versus CROs and whether they are getting the best value for money. Companies lack a good way to measure whether studies are being done in an efficient, cost-effective way compared to their peers. Abramson said he always wants to deliver studies on time and within budget. Yet he worries less about the logistics of having enough money to fund a particular study and more about how overspending could limit the ability to fund additional studies for drugs that could benefit patients.

“The more efficiently we run and operate our studies, the more studies we would be able to do. If we run studies ineffectively, we will be forced to more aggressively prioritize the portfolio of studies, potentially missing really important studies,” he said. “If we have a fixed pool of money to draw upon for clinical trials, how do we effectively use that money to the greatest benefit of society and the company? To me, it gets back to very core issues of why we do what we do and the significance of how we do it.”

Solving study startup and data quality issues

Barbara Tardiff, M.D., vice president of development operations for worldwide research and development at Pfizer, has worked in clinical research and drug development operations for the past 20 years at various types of organizations, including the Duke Clinical Research Institute, biotechnology companies, CROs and pharmaceutical companies. At every place where she has worked, the same two issues have persistently kept her awake at night: Why hasn’t the industry been able to fully solve problems around study startup and data quality?

Despite the fact that sponsor companies have opened many thousands of clinical studies throughout the years, Tardiff said the mechanics of study startup are still highly inefficient and unpredictable. A great deal of time and money is spent on identifying, qualifying and initiating investigative sites. Many companies negotiate clinical trial agreements separately with each principal investigator, a burdensome and time-consuming process that results in study contracts that lack uniformity.

“It feels like we are always starting from scratch. We go through all of these different steps over and over again, and then multiply it by the number of investigators in a study,” said Tardiff. “It’s the complete opposite from something being an assembly-line production or repeatable. There is a lot of uncertainty. It astounds me that we haven’t solved this problem and that it’s something that still takes so much time and energy.”

Tardiff has become even more concerned about inefficiencies in the study startup phase as the industry moves toward a precision-medicine approach to clinical trials. The economics of drug development change dramatically if a company needs to start up hundreds of sites, at costs of up to $30,000 each, in order to enroll a very select group of patients for a precision-medicine study. Development costs also could be higher since more scientific assays and tests would be required.

“You couple that with the lower revenue opportunities because of the smaller market size and the economics just don’t make sense. We’ve got to figure out how to make the startup take less time and money, use fewer resources and be more predictable. A whole redesign is needed. We need to approach this in a completely different way,” said Tardiff, who believes the industry needs to move away from site-by-site strategies and approach startup on a systematic level. “How do we get to it so that once you get a protocol, it just goes into action?”

Another industry-wide issue, the need to ensure the reliability of data quality, also keeps Tardiff up at night. While a great deal of attention has been focused on monitoring data collection and quality at sites, she has long been concerned about the potential for introducing errors or missing information as raw data goes through the multiple steps required to transform it into formats used to evaluate the safety and efficacy of drugs. In addition, the volume of data collected has grown exponentially—clinical study reports today typically contain thousands of tables—yet approaches to validate the data haven’t evolved significantly during the past two decades.

“The more volume you do, the more chance there is for error and the more things you have to inspect,” said Tardiff. “The approaches that have worked in the past, such as checking and double-checking, don’t work now because no company has the resources to do it that way. Yet nobody wants to make a mistake in judging safety and efficacy. There is a lot of anxiety about it. Data is really the soul of what we’re doing and being able to get a view of the data is harder because there is so much raw data. We need to step back and look at the issue.”

Finding the right outsourcing model

Like many other clinical operations executives, Josephine Cucchiaro, Ph.D., head of global clinical operations at Sunovion Pharmaceuticals, spends a great deal of time thinking about the right mix of outsourced and in-house staff based on the company’s work culture, size, cost pressures and global development needs.

Sunovion, which is based in Marlborough, Mass., traditionally has outsourced 100% of monitoring activities for the studies it manages globally. The U.S. clinical operations group recently began to align its model with colleagues in Japan, where conventional in-house clinical research associates (CRAs) are employed to visit study sites. Efforts also are underway to establish strategic alliances with two or three global CROs that can support the company’s clinical operations needs, including a presence in Japan, since the partnership model can lead to greater operational efficiencies compared to transactional outsourcing.

As a small company that doesn’t have clinical operations staff in most countries overseas, Cucchiaro said outsourcing will always be necessary for global studies. Yet at the same time, Cucchiaro is establishing a small group of in-house monitors in the U.S. to specialize in risk-based monitoring and early-phase or small studies that have a few number of sites, an approach that can offer cost savings compared to hiring a global CRO for specific types of studies. Plans call for an eventual introduction of the in-house, risk-based monitoring model in Japan.

“The industry is generally moving toward a more outsourced model. Yet I think the pendulum always will swing. Some employers are looking for heads of operation who will bring everything in-house,” said Cucchiaro, who has more than 20 years of experience in the pharmaceutical industry. “I think 100% outsourced isn’t necessarily good and 100% insourced isn’t good. The question is: What is the right ratio? This keeps me up at night. I worry about the right ratio, especially as we move toward risk-based monitoring, where there will be less need for people to go to the sites and the number of monitors will be lower.”

Cucchiaro, who has been involved in CNS clinical development for some 20 years, also spends a great deal of time thinking about difficulties that sponsor companies industry-wide have encountered in placebo separation, or trying to demonstrate a statistically significant difference between study drug and placebo, in CNS clinical trials conducted in the U.S. Sunovion specializes in developing products for CNS and respiratory conditions.

“I don’t know how to crack the nut,” said Cucchiaro. “Are there too many sites and too much variability introduced by them? Is it just a few sites that are not doing well that are sinking the rest of them? Is it the patients who are no longer responsive to antipsychotic drugs because they have already been exposed to several others in the class? We have to understand these issues to have successful clinical studies in CNS.”

In Cucchiaro’s mind, questions about placebo separation in CNS trials also tie into ongoing concerns about patient recruitment. How do you recruit the right patients? Where do they come from? How do you get them? And as you move ahead with modern technology, should you use social media? Does it work? Cucchiaro also contemplates ways to give patients better access to clinical trial opportunities through embedding research at smaller, local sites and thinks about fundamental issues concerning how to build greater public trust in the clinical research enterprise.

“We need to convince a broader population that we have a social responsibility to participate in trials so that we can find new, effective medicines. We can’t find medicines if people are unwilling to step up and participate,” she said. “We need to remove the stigma, fear and mystery from clinical research. We need to figure out a way to make clinical study participation more acceptable so more people will understand the importance of trial participation to them and to our future.”

Sourcing studies

From an overall perspective, Andy Lee, senior vice president and head of global clinical trial operations at Merck, sees that the operational logistics for conducting clinical trials have become more complex as sponsor companies are faced with cost, speed and quality pressures in a highly competitive and regulated environment.

In addition, clinical operations have become more complicated as Merck and other companies have put a larger focus on developing biologic products, such as cancer immunotherapies that can have large clinical effect sizes; such studies are typically more expensive than those conducted with chemically manufactured small molecules. Biologic products by nature require careful handling during manufacturing and distribution in well-controlled temperature ranges, and they also have the added complexity of requiring complex devices like autoinjectors to deliver the appropriate dose.

“The competitive world, the regulatory world and the challenges of the new scientific approaches to manage disease has led to increasing complexity in our world,” said Lee, who has 20 years of experience conducting clinical trials. “Among those areas, you can pick your day and there are many things that, from my perspective, keep me awake at night.”

One constant worry is whether there will be enough qualified field monitors available with the skills necessary to run studies in the right geographic locations and at the right time. Although companies consult predictive analytics when planning clinical trials, in a competitive world, it’s not always easy to forecast where resources will be lacking or in abundance. Lee said the industry is facing a huge shortfall in skilled monitoring resources (CRAs), which is something that it should address collectively.

“For Merck, monitoring is a core competence. As an industry, we need to focus on the value that CRAs bring and we need to collectively solve this problem by investing in training and investing in the importance of these positions,” said Lee. “If we can get the monitoring right, we can tackle some of the common themes around risk that the industry is experiencing, such as re-consenting patients, protocol deviations, maintaining trial master files, and the adequacy of field monitoring to detect and correct deviations.”

Implementing new technology systems is another area of critical concern. The clinical research space has adapted and accelerated use of information technology (IT) and electronic systems, which can help expedite trials and reduce waste. Yet clinical operations groups struggle with how to industrialize those tools in ways that maintain security and privacy. The difficulty in finding interoperable systems that can run enterprise-wide also keeps Lee up at night.

“It’s a challenge getting new systems that are validated, secure and interconnected. There are multiple disparate systems,” said Lee. “I worry about this because any failure in electronic systems can lead to lack of compliance. We could lose data or we could struggle to maintain compliance with very tight reporting requirements.”

Significantly, Lee said clinical operations practices at his company are going through a “massive paradigm shift” as advances in drug discovery and development, particularly for targeted therapies, have resulted in drugs that show signs of extraordinary effect size or benefit at early stages of testing. Merck, which focuses on treatments that have large effect sizes and meet unmet medical needs, has developed products in hepatitis C and cancer that the FDA has designated as Breakthrough Therapies, which could help expedite development and review times. The breakthrough status sometimes comes from an interim analysis of trial data, which could trigger an inspection within days of submission, and means that the operational staff needs to prepare in advance for inspections rather than waiting until after the trial is finished.

“When we get expedited review, what this means to me is an expedited inspection,” said Lee.

“It’s changed the nature of our work in that we have to be contemporaneous with our data, our monitoring in the field, data querying and data cleaning, and the scans and lab assessments done in third-party labs. We have to be ready to cut the data and supply it in real time and to defend inspections in real time.

“Since we have to be contemporaneous, rather than lagging, that makes us think about how we design studies, manage studies and how we get efficiencies in making sure our trial master files, data managing and monitoring is all up to date. It requires a different set of resources and a different set of planning. We are planning for expedited success.”

Looking forward

The interviews with clinical operations executives about issues that occupy their thinking offer many insights for stakeholders and service providers looking for unique opportunities to better serve clinical operations teams. Finding ways to effectively embed clinical research in remote communities, for example, or approaches that could connect more patients with appropriate study opportunities offer the potential to transform patient recruitment practices.

Redesigning the study startup process to operate on a systematic level, rather than on a site-by-site basis, could allow studies to start more quickly and more effectively. In another example, better training programs and efforts to place higher value on the work that study monitors perform could help address concerns about the global shortage of study monitors.

Taking steps to address the concerns that clinical operations executives feel are most pressing can result in more efficient, higher-quality clinical trials that ultimately can bring new drugs to patients more quickly. 

 

Karyn Korieth has been covering the clinical trials industry for CenterWatch since 2003. Her 30-year journalism career includes work in local news, the healthcare industry and national magazines. Karyn holds a Master of Science degree from the Columbia University Graduate School of Journalism. Email karyn.korieth@centerwatch.com.

This article was reprinted from Volume 22, Issue 10, of The CenterWatch Monthly, an industry leading publication providing hard-hitting, authoritative business and financial coverage of the clinical research space. Subscribe >>