How Can You Manage the Complexity of Early Phase Clinical Development?

In the ever-evolving landscape of pharmaceutical development, the complexity of early phase clinical trials is increasing. This surge in complexity is driven by escalating drug development costs, heightened competition and advanced scientific innovations.

In this Xtalks Spotlight feature, Oren Cohen, MD, Chief Medical Officer (CMO) and President of Clinical Pharmacology at Fortrea shared insights into these challenges and the strategies Fortrea employs to manage them efficiently. Dr. Cohen has served in this position since Fortrea’s launch as an independent company in July 2023 following its spinoff from Labcorp.

Fortrea is a provider of comprehensive Phase I through IV clinical trial management, clinical pharmacology, market access solutions and other enabling services. The company partners with small and large biopharma and medical device and diagnostic companies to optimize early clinical development through excellence in study design and execution.

“There’s a lot of great science now, but every company with an interesting asset is kind of under the gun to prove its point earlier and earlier. The earlier the better.”

— Dr. Cohen

Dr. Cohen speaks about the significant increase in complexity in the early clinical space, discussing factors including increasing development costs and increasing complexity of molecules and resulting trial designs. With increased complexity comes increased risk management ensuring patient safety whilst maintaining the collection of robust data.

Escalating Costs and Increasing Complexity

As with any industry, increasing costs and financial pressures are impacting the pharmaceutical, biotechnology and medical device industries. The cost of developing a new drug is tipping the $2 billion mark per asset, putting immense pressure on the internal rate of return for pharmaceutical companies. This mammoth financial investment is exacerbated by a downward trend in returns seen over the past ten to 15 years, despite some recent recovery.

As Dr. Cohen points out, this current drug development landscape fuels intense competition among companies, each striving to prove the viability of their assets earlier in the development process to secure funding and continuation of development.

“There’s a lot of great science now, but every company with an interesting asset is kind of under the gun to prove its point earlier and earlier. The earlier the better,” says Dr. Cohen. He explains how he believes this is driving “protocols that are packed with complexity, trying to get more and more answers at an earlier and earlier stage. And that has a lot of downstream consequences.”

Moreover, company acquisitions have been playing an increasing role in adding to the complexity and cost of drug development. Small biotech companies, often at the forefront of innovation, are commanding astronomical acquisition prices based on promising early data for strong assets. This trend, which Dr. Cohen says might have begun with hepatitis C drugs over a decade ago, continues to drive up costs and competition, further complicating early phase clinical trials.

“The pressure cooker of competition and high costs is driving complexity to try to get earlier and earlier insights into a drug’s prospect. This is the storm that we find ourselves in the midst of.”

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Manifestations of Complexity in Clinical Protocols

Dr. Cohen describes how this increased complexity manifests in the design of study protocols, which have changed over the last ten to 15 years.

Traditionally, early clinical development involved straightforward, sequential stages such as first-in-human (FIH) single ascending dose (SAD) followed by multiple ascending dose (MAD) studies. There was therefore a concurrent series of studies to progress through, accumulating data and deepening asset understanding. However, current protocols often combine these stages with additional components like food effect studies, drug-drug interaction assessments and different patient cohorts (in addition to normal healthy volunteers in the earlier phases of a study). This amalgamation, which could have constituted multiple separate studies a decade ago, now forms a single, intricate but complex protocol.

“The multiple components run through enormous complexity wrapped up with a bow in one single protocol. A decade ago, what might have been five or six separate studies, are now all rolled into one.” This leads to a “scramble to get earlier and earlier insights,” explains Dr. Cohen.

The intellectual property involved in these trials has also become more complex. The drugs tested today are substantially more complex due to the science being more complex, often involving sophisticated mechanisms of action, such as intricate immunologic signaling cascades. In the past, the majority of drugs evaluated in the clinical pharmacology space were small molecules. Today, there’s been a shift towards more complex, large molecules or biologics like monoclonal antibodies, antibody-drug conjugates (ADCs) and advanced therapies like RNA-based treatments and cell and gene therapies.

More sophisticated molecules coupled with increasingly complex trial designs “leads to a lot of complexity to deal with. Our mission at Fortrea is to deal with and manage the complexity in the space,” says Dr. Cohen.

Strategies for Managing Complexity

To address these challenges, Fortrea has re-engineered its approach to conducting studies. Dr. Cohen explains that whereas clinical pharmacology once centered around a single clinical pharmacology unit, it now involves multiple clinics and external sites. This shift necessitates a new project management approach, focusing on multi-site management rather than site-specific oversight.

It has become more common to work on one study across multiple clinics, which could be Fortrea clinics, external sites or a combination of them, explains Dr. Cohen.

Additionally, project management methodologies have changed drastically and are no longer site based as studies frequently have multiple sites now. As a result, project management groups manage studies in a site agnostic way, which is fit for purpose in terms of protocol design.

Investments in fit-for-purpose infrastructure have been pivotal in managing the increased complexity. Dr. Cohen says this new infrastructure has been unveiled at Fortrea’s Leeds location in the UK and expanded to a couple of US clinics to include new Current Good Manufacturing Practice (CGMP) pharmacies. The company has developed new clinics designed specifically for modern clinical pharmacology protocols and expanded its digital capabilities with a bedside data capture system to replace paper-based trials. These changes, particularly the shift to fully digital spaces, facilitate more efficient and precise management of complex trials.

This is some of the tool set that has radically changed the picture of how clinical pharmacology studies are done these days, says Dr. Cohen. He says it’s been a journey, with great results in the “ability to manage enormous complexity in the space to get important trials done in an efficient and precise way that yields the data needed to make good decisions.”

Proactive Risk Management

When discussing risk management in early phase clinical trials, Dr. Cohen emphasizes the unique nature of the studies compared to later phases.

Dr. Cohen explains that just as “pediatricians say kids are not small adults, I say to my later phase drug development colleagues that clinical pharmacology studies are not just small phase III trials. They are unique and require specific expertise.”

FIH studies involve a lot of risk. They include skilled investigators, nurses and technicians, and “our heroic study volunteers agreeing to participate in these medical experiments. There’s a lot of testing, which is part of the experiment, that goes into ensuring safety. This requires not only fit-for-purpose infrastructure, but a dedicated skillset.”

“It’s a special responsibility to undertake these experiments in humans that pose risk.”

Risk is managed in early phase trials by using the failure modes and effects analysis (FMEA), a tried and true, proactive method widely used in high-risk industries that involves detailed analysis of study protocols. This rigorous process helps identify potential risks and establish mitigation strategies before the trial begins, ensuring the safety and well-being of participants.

It includes detailed consideration of potential complications ranging from the use of complicated dosing devices to the specifics of sample collection for biomarkers or pharmacokinetic assays. It also involves ensuring appropriate storage conditions to gather essential data. This is all done to protect the safety and well-being of research subjects, which is always paramount.

Dr. Cohen believes using robust risk management methodologies like FMEA is “incumbent on us and everybody should do it to wring out and mitigate risk in advance as much as possible,” noting that a wise person once said, ‘an ounce of prevention is worth a pound of cure.’

The ever-deepening complexity of early phase clinical trials is being addressed through a combination of strategies. These include strategic fit-for-purpose infrastructure investments, innovative management strategies and proactive risk assessment, supporting the development of groundbreaking therapies and bringing them to market efficiently and safely.

This article was created in collaboration with the sponsoring company and the Xtalks editorial team.