How Pharma Needs to Prepare for the Next Pandemic

April 26, 2023

Article

Master protocols helped accelerate research during the pandemic in the EU. How can US companies learn from this and start preparing master protocols now?

Derk Arts, MD, PhD

Craig Lipset

The COVID-19 pandemic is often referred to as a “once in a lifetime” event. But modeling work based on historical data¹ shows that this may be an overly optimistic viewpoint. As a 2021 research article² pointed out, “increasing rates of disease emergence from animal reservoirs associated with environmental change”³ may contribute to the likelihood of future pandemics similar to COVID-19—a risk that may double in the coming decades.

Research readiness at a standstill

Even more sobering than the threat of another global health crisis is how little has changed in clinical research readiness since pre-COVID-19. Most of what was perceived as success at the start of the pandemic in the US was rooted in the federal government deploying $11B to 8 companies for vaccine development under Operation Warp Speed⁴ in August 2020. Funding of advanced purchase orders⁵ further derisked and created aligned economic incentives; however, this is hardly a sustainable model.

Meanwhile, the pandemic saw the whole-scale embrace of decentralized clinical trials (DCT). While DCT offers many advantages,⁶ it is by no means a new concept.⁷ So what was the holdup? A perceived risk of innovation. Only the greater risk of a viral exposure shutting down studies pushed pharma to view the status quo as a greater operational risk than DCT.

Suddenly, DCT became a risk mitigator that allowed business continuity in an uncertain environment, offering the perks of improved experience, access, and representation. But now, as we enter the “new normal,” we’re seeing its adoption stall out.

While the progress made during the pandemic is noteworthy, it is tenuous at best. Without a commitment to continued progress, there is a real risk of slipping backward. Progress comes in many forms, whether it’s data standardization, continued use of DCTs, increased public awareness of clinical research, or adoption of new models like the master protocol.

One of these innovations, the master protocol, succeeded in Europe but failed to be fully implemented in the US. Taking time to understand this new way of looking at clinical trials, getting key stakeholders on board, and implementing practical steps to take now can help US pharma companies prepare for the next global health crisis.

The role of master protocols

When a crisis hits, it takes time to get people aligned. Clinical research is no different. During the COVID-19 pandemic, we saw many pharma companies exemplify the phrase: “If you want to go fast, go alone but if you want to go far, go together.” During the pandemic, many trials eschewed “going together” via master protocols to go alone faster.

For example, Moderna and Pfizer ran nearly identical mRNA studies on a simultaneous timeline. In hindsight, these could have been combined into a collaborative master study with three arms. Perhaps this would have been faster. It certainly would have been more efficient and supported expert collaboration.

Master protocols could play an important role in⁸ aligning researchers during a future health crisis. Master protocols include multiple sub-studies within the same overall trial structure or a customized trial network. For example, a master protocol with an umbrella design⁹ could compare several drugs or drug combinations alongside a control for a disease.

Because the trials share design components and operational aspects, carefully combining them allows researchers to answer more than one question without the cost and time needed to conduct completely different studies. Master protocols can also be reused,¹⁰ providing an opportunity for continuous learning.

Developing master trial protocols for a potential therapeutics and vaccine trial ensures the research teams are ready to act quickly when a new pandemic occurs. They also ensure that the research will be conducted in an ethical and efficient manner, regardless of any clinical urgency.

US slow to adopt master protocols

WHO had a master protocol¹¹ available during the COVID-19 pandemic. It was not utilized in the US, though, with researchers and pharma companies instead choosing to work independently from one another. This led to many underpowered studies unable to answer meaningful questions on best treatments.

Meanwhile, in Europe, there was greater use of master protocols. For example, the Solidarity trials¹² offered a platform for umbrella trials aiming to identify treatments and vaccines for COVID-19, with more than 35,000 patients randomized and 5,100 investigators at 550 hospitals across 30 countries. Similarly, the RECOVERY trial¹³ recruited 48,465 participants at 195 active sites.

In the US, future success depends on pharma companies collaborating on master protocols. Success also depends on ensuring incentives are aligned so that they are utilized. For example, funding sources could require new research to run on existing platform trial infrastructure wherever possible. Regulatory bodies like FDA have expressed support for this approach.¹⁴

Creating a master protocol

Although master protocols can accelerate drug development by gathering large amounts of information and sharing infrastructure for efficiency, they are often more complex to design. That’s why pharma companies need to make plans now.

Pharma companies can begin developing master protocols by reviewing FDA guidance¹⁵ published in 2021. FDA includes many helpful recommendations in their guidance specific to lessons learned during the pandemic, including:

Starting with a randomized comparator arm to mitigate confounding variables
Protecting ongoing results from one sub-study from impacting how researchers approach another sub-study
Onsite training to counter the increased risk of protocol deviations
Developing a robust communication strategy for safety concerns

Pharma companies can approach designing their master protocol in three phases:¹⁶ pre-planning, planning, and execution. Now is the time to start working on the pre-planning and planning phases.

Pre-planning phase

Although pharma companies can’t work on a scientific rationale for a disease that hasn’t manifested, they can create space in their plan to fill in this information later. They will need to identify the natural history of the disease,¹⁶ related biomarkers, underlying disease biology, available drugs, and the number of drugs that can be studied concurrently. Preparing to investigate these things will help companies take action when the next disaster occurs.

Pharma companies can also lay the groundwork for the master protocol during the pre-planning phase. This involves everything from developing a business plan to outlining the governance structure for the study and identifying the appropriate regulatory bodies. Working closely with regulatory bodies¹⁵ is integral to a successful master protocol. During the pre-planning phase, pharma companies must consider essentials like budget, funding, data safety, publication oversight, and stakeholder engagement.

Planning phase

Pharma companies work closely with stakeholders during the planning phase16 to design the studies, develop an operational model, choose appropriate software, decide how investigators communicate results, build governance structures, and train staff. Companies can use lessons learned during the pandemic, such as the efficiency of DCTs, to take full advantage of innovative tools.

Execution phase

COVD-19 taught the clinical research industry to expect change as the only constant during a global health crisis. Pharma companies can anticipate modifying their master protocol substantially as the study progresses to adjust to new clinical and scientific findings.

Signs of progress

Perhaps the best sign that pandemic learnings like implementing master protocols will have a lasting impact on clinical research is the US government’s increased awareness. In October 2022, the federal government requested information on clinical research infrastructure and emergency clinical trials.¹⁷ They also asked for information on data collection for emergency clinical trials and interoperability pilot.¹⁸

After reviewing these requests, it’s our opinion that the US government is asking the right questions. This is hopeful since it indicates maturation in their way of addressing stubborn problems within clinical research.

The time for action is now

Some may say this isn’t the moment to push forward the innovation required. After all, the industry’s foundation may even seem unsteady, with investor-backed tech companies refocusing on profitability and retaining talent and perceived reimbursement challenges on the horizon.

Despite these challenges, pharma must press forward to prepare for the next global health crisis. With the support of regulatory bodies and other key stakeholders, we can start investing time and effort into preparing master protocols. Otherwise, we risk accumulating innovation without actual adoption.

Lacking meaningful action, we may find ourselves back in the throes of a global health crisis, having learned nothing of the lessons COVID-19 offered us.

Derk Arts, MD, PhD, CEO, Castor, and Craig Lipset, advisor and founder, Clinical Innovation Partners

References