Improving The Clinical Trial Ecosystem: A Call To Stakeholder Alignment

By Rob Freishtat

We live in an era of extraordinary scientific advancement, and as a result, we are seeing rapid growth in the development of new drugs. When the clinical trial ecosystem works, we deliver on our promise as an industry to help patients -- especially those with rare and complex diseases. But when the ecosystem grinds to a halt because of misaligned incentives or bureaucracy, what should become opportunities to break through can instead become moments of breakdown.

In theory, all of the stakeholders in drug development — investors, scientists, regulators, and patients — share the common goal of creating safe and effective drugs. Patients want effective drugs. Scientists want to improve human health. Regulators want the study process to be safe. Investors want a return on the investment that comes from successful trials. And when a drug gets approved, goes to market, generates a return on investment, and works as it should work, everyone is happy. And yet, over time, misaligned incentives have still found their way into the system and gummed up the works. But why? How did we get here? And what can we do about it?

The Roots of Our Misalignment

Interestingly, the growth and success of drug development, which has given us so many breakthrough cures, has also given rise to an expanded infrastructure and bureaucracy around that growth. Over time, we have seen the drug trial process accrue an ever-increasing number of procedures, regulations, and third-party operators, each piece of which has its own set of requirements; some of which are actual external requirements, while others are self-imposed. While some of this additional process can add value or serve important ethical, procedural, and safety purposes, much of this added process and complexity simply adds … more process and complexity. 

It is in this environment of ever-increasing complexity where misaligned incentives can emerge and derail the process. We may see misalignment crop up when people or processes that are not intrinsic to drug development start to drive how things are done rather than keeping our shared mission of creating great drugs in the driver’s seat. We may see it sneak in when regulations over-correct for past mistakes and dramatically slow down study processes. Or we may see it arise whenever busy work and “doing things like we always do them” trumps collaboration and innovative thinking. Any time we leave people to operate in silos at the expense of collaboration, over-complicate protocols, or find ourselves simply doing things as they’ve always been done, we run the risk of creating needless friction and busy work, leaving stakeholders seemingly at odds with each other.

And therein lies the rub: Our best intentions to keep trials safe and effective have, over time, added multiple layers of complexity and process that can backfire and sometimes keep us from our goal of developing great drugs.

Examples of Misaligned Incentives

To better understand how these misalignments emerge, let’s consider a couple of common examples:

Study overdesign: I often see studies proposed that require more patients for the study than there are patients who would meet the proposed inclusion and exclusion criteria. This commonly occurs in rare disease trials because the study designers are personally incentivized to do things the way they have always been done, i.e., nobody is likely to get fired for proposing the tried-and-true double-blind placebo-controlled randomized clinical trial. However, this study design for a rare disease trial is probably doomed from the start. Sure, if you’re testing a hypertension drug and have millions of people who might participate, no problem. But, for most rare diseases you might struggle to find two dozen eligible and willing patients. If your study design requires 100 patients but the population of people with the disease who meet the inclusion and exclusion criteria is 30, that’s a non-starter. In situations like this, we need to use alternative designs that are equally valid but are much more powerful at detecting differences using far fewer patients. We need to incentivize innovation so that studies are driven to align their design to the needs of the study at hand, not defer to the way things have always been done.

Regulator-phobia: For a variety of reasons, many in the clinical trial field harbor a fear of regulators. The resulting lack of communication between stakeholders and regulators has led to frequently incorrect assumptions about requirements, and layer upon layer of processes to ensure compliance. Like a child wanting five band-aids on a tiny knee scrape, it is common to see companies insist the FDA requires more than 300 standard operating procedures for a clinical trial. While these are important documents that help us keep patients safe while running an effective trial, we know from discussions with the FDA that the actual requirement is around 40. So where did these other 260 come from? They are band-aids on that child’s knee: each an attempt to comply with an assumed requirement incentivized by fear of running afoul of regulators. It is overkill. The thinking is, if we follow the same structure as last time, everyone and everything will be protected under the umbrella of risk-avoidance. But sometimes, that comes at the expense of solution-seeking.

These examples illustrate a couple of ways misaligned incentives result in a process that is seldom examined and balloons over time, even if it is well-intentioned. If we don’t incentivize fresh, creative thinking, all we’ll get is copy/paste with additional layers. What we want to see are more efficient study designs that will allow new drugs to get through the regulatory process both cheaper and faster. And that will benefit all of the stakeholders at every stage, especially patients.

We cannot lay the blame for these misalignments at any one individual’s feet. It is an issue that has built up over time. What we can do is take the initiative and responsibility for finding innovative solutions. Fixing these gummed up parts of the system is what lights me up as a professional. How can we resolve these seemingly misaligned incentives and apparent internal contradictions? How can we tease out which new layers and tasks add value, and which do not? How can we ensure that our charge to make drug development safe for study participants is in service to and in alignment with our primary, driving goal of creating great drugs that will improve the lives of patients everywhere? 

Moving Together in One Direction

It is in this spirit, one of inquiry, collaboration, and alignment, that we must approach the future of clinical trials and drug development. It is the interconnected nature of this work that makes stakeholder alignment so critical. Indeed, misaligned incentives for any stakeholder will ripple across every phase of drug development. While there is much to be done and it will take time, I recommend a few key (and simple) strategies to begin:

• Maintaining Mission Focus At Every Level: Being mission focused is critical to alignment, and engaging leaders to share a unified mission is essential. By clearly articulating the overall mission and maintaining focus on the end goal — namely, bringing safe, effective drugs to patients — leaders can inspire their teams to align their efforts. Regular communication and transparency about the progress and challenges can help keep everyone on track.
• Embracing Partnerships In Practice, Not Just In Name: External partners need to truly be partners, not just service providers or cogs. Treating these entities as trusted extensions of the internal team, rather than consultants or vendors, can enhance collaboration and innovation. Companies should seek partners willing to challenge traditional approaches and suggest improvements, ensuring that study designs and trial implementations are robust and effective.
• Cultivating Flexibility And Openness To Feedback Between All Stakeholders: Engaging with regulators early and often — and treating their feedback as a valuable resource rather than a hurdle — can streamline the approval process and increase the likelihood of success. This kind of proactive communication, particularly with regulatory bodies like the FDA, can prevent costly missteps. 
• Encouraging Innovative Thinking At Every Stage: What is the answer to moving beyond stale, outdated thinking? New thinking. We need to encourage experts at each stage to think deeply and creatively about how they can leverage their expertise to find new, efficient solutions, not just to keep doing things as they’ve always been done.
• Prioritize Aligning Incentives For All Stakeholders: Finally, we need to prioritize the alignment of incentives across the ecosystem over self-protection and isolationist thinking. It is crucial that we work together, share expertise, and collaborate for the sake of the shared mission. This will improve not just patient and study outcomes but the future of our industry as a whole.

As we find ourselves in this era of extraordinary scientific advancement, we must do all we can as an industry to make it also an era of alignment. We must address the frictions and challenges that have quietly infiltrated our clinical trial ecosystem and root them out, planting instead a new spirit of partnership and collaboration. Rather than allowing business as usual, misaligned incentives, or bureaucracy to take the driver’s seat, we must let innovation and mission guide our decisions. 

This kind of systemic change won’t be easy or happen overnight. It will require changes, both big and small. The good news is that it is within our power as an industry to turn moments of breakdown back into moments of breakthrough. We all want the clinical trial ecosystem to create effective drugs for patients. Let’s make sure that we are doing all we can to make it happen.

About The Author:

Rob Freishtat, MD, MPH, is the President and Co-Founder of Uncommon Cures, where he leads the development of innovative clinical trial programs for rare diseases on a global scale. He holds a Doctor of Medicine (MD) from the University of Maryland and a Master of Public Health (MPH) from George Washington University.