Navigating uncertainty in modern clinical development
15 May 2023
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Source: FierceBiotech
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Author: Dr Albert Kim, Chief Medical Officer, Cytel
Developing a new life-saving drug or medical device is fraught with challenges. But while challenges often vary from program to program, one in particular is guaranteed: uncertainty. In this article, Dr Kim, CMO at Cytel, discusses the nature and consequences of the uncertainty challenge, as well as the options available to help pharmaceutical and biotechnology companies navigate it.
Imperfect data and huge uncertainty — par for the course in modern clinical development
Uncertainty and imperfect data accompany all projects at every stage of the development journey. For example, at the scientific bench, companies must address a series of technical questions around how their potential therapies operate mechanistically and how they interact with animal or human physiology. Once those questions are addressed and the new medicine or device migrates to clinical development, companies face another set of equally challenging questions: will this product help people feel better, function better, or survive longer? How should we measure these potential benefits compared with potential safety concerns?
Regulatory questions come into play, too, aimed at discharging uncertainty around a therapy’s benefit-risk proposition. And then, finally, companies must address unknowns regarding reimbursement — how will people pay for the product? Will patients, insurers, or the government pay?
A key challenge is navigating this incredibly complex, uncertain landscape: which unknowns should companies tackle first? How are companies to make clear decisions when considering numerous risks? Moreover, companies often have no set road map for the journey. But even where companies do have an existing, well-trodden road to follow, they have no guarantee the same path others used will work for them.
Uncontained uncertainty: consequences for your program
The consequences of uncertainty can be significant and highly variable. Broadly, the scope of consequences can be compared to trying to build a new house without a good plan: it may lead to unexpected and unwanted results, such as corners that don’t meet, or inadequate heating. In clinical development, analogous unexpected results could take the form of a clinical trial that delivers ambiguous data or data that doesn’t convince patients or payers.
What’s more, while uncertainty provides the freedom to pursue any path, it also means that path may not take you closer to your overall goals. That’s something sponsors can’t afford in a competitive landscape.
Key considerations, tools, and approaches for success
Despite the familiarity of these challenges, knowing how to approach them is difficult — neat answers and solutions don’t always exist. But that’s not to say companies don’t have a host of approaches available to help them better grapple with uncertainty.
One of the most important steps companies can take is to outline exactly what their strategic priorities are. These priorities directly impact which uncertainties you should discharge, and when. It’s also important to create — and stick to — a plan that can help you realize these goals. Furthermore, since many surprises should be expected during product development, the plan must be accordingly flexible. That's why Cytel pioneered the science of adaptive clinical trial design, enabling companies to account for the volatility of modern clinical development.
Looking more closely at planning, several tools can help analyze the impact of trade-offs as part of creating a plan. Companies can now quantitate and clearly visualize trade-offs, such as power vs. speed, thanks to approaches like simulation-guided trial design. These approaches let you more confidently identify the best path or strategy during product development — which isn’t always the one you instinctively prefer. Having supported many sponsors to quantitate trade-offs in terms of cost, money, and statistical power, Cytel has witnessed the value of such strategic visualization firsthand.
Finally, thinking probabilistically can also hugely help companies traverse uncertain territory. When probabilistic thinking is applied to data decisions in the form of Bayesian frameworks, it offers immense value. For example, a critical challenge in clinical development is the reproducibility of promising early clinical data in later trials. How can you know your promising early data will be confirmed in larger studies? What is the true treatment effect? Bayesian probability frameworks can help to clarify how confidently you can answer these types of questions.
Trusted thought partners can ease the path to more confident decision-making
In addition to considering the approaches and tools mentioned above, companies can find significant value in working with trusted, collaborative thought partners with deep and varied development experience. Such collaborators can help in at least three ways.
First, they can help companies develop and implement a framework aligned with their strategic priorities. Second, they can provide objectivity. In any decision-making process, people bring biases to the table. A trusted third party can help identify those biases and flag blind spots that could derail a program.
Third, collaboration partners can bring complementary expertise and additional technical resources to augment a sponsor’s team and problem-solving toolbox. Even the most well-equipped and experienced teams can benefit from the right partner. When traveling on vacation, you may think you know a city very well from prior visits, but having access to a local resident’s knowledge can provide incredible insights that make a visit truly special.
Securing a smoother route through uncertainty
It is no secret that companies must make decisions with incomplete data or considerable uncertainty during development. And companies are well aware that inadequately understanding and accounting for these uncertainties can lead to unsatisfying results, wasted time, and low return on investment.
Even in areas of great uncertainty, companies should know that a number of tools and approaches are available to provide much needed clarity.
With the right team and the right quantitative approach, sponsors can better survey the risk landscape, put boundaries around their uncertainties, and make more confident decisions to maximize their chances of success.
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