Derk Arts, MD, PhD

The COVID-19 pandemic is often referred to as a “once in a lifetime” event. But modeling work based on historical data

 shows that this may be an overly optimistic viewpoint. As a 2021 research article

 pointed out, “increasing rates of disease emergence from animal reservoirs associated with environmental change”

 may contribute to the likelihood of future pandemics similar to COVID-19—a risk that may double in the coming decades.

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 Speed

 in August 2020. Funding of advanced purchase orders

 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,

 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.

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 in

 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 design

 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,

 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.

 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 trials

 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 trial

 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.

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 guidance

 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:

 pre-planning, planning, and execution. Now is the time to start working on the pre-planning and planning phases.

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,

 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 bodies

 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.

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.

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.

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.

 They also asked for information on data collection for emergency clinical trials and interoperability pilot.

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.

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.

, advisor and founder, Clinical Innovation Partners

https://www.cgdev.org/blog/the-next-pandemic-could-come-soon-and-be-deadlier

https://www.pnas.org/doi/10.1073/pnas.2105482118#executive-summary-abstract

https://www.statnews.com/2023/03/15/climate-change-diseases-west-nile-dengue-lyme/

https://www.statnews.com/2020/09/08/operation-warp-speed-promised-to-do-the-impossible-how-far-has-it-come/

https://www.defense.gov/News/Releases/Release/Article/2310994/us-government-engages-pfizer-to-produce-millions-of-doses-of-covid-19-vaccine/

https://www.statnews.com/2021/01/29/decentralized-clinical-trials-more-collaboration-needed-to-expand/

https://pubmed.ncbi.nlm.nih.gov/24792229/

https://www.nejm.org/doi/10.1056/NEJMra1510062?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200www.ncbi.nlm.nih.gov

https://www.sciencedirect.com/science/article/pii/S2451865420300521

https://cms.centerwatch.com/articles/25624-use-of-master-protocols-expected-to-grow-in-wake-of-fda-guidance

https://onlinelibrary.wiley.com/doi/10.1111/irv.12915

https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments

https://www.fda.gov/news-events/press-announcements/fda-brief-fda-provides-guidance-master-protocols-evaluating-prevention-treatment-options-covid-19

https://ctti-clinicaltrials.org/wp-content/uploads/2021/06/CTTI_Master_Protocol_Roadmap.pdf

https://www.federalregister.gov/documents/2022/10/26/2022-23110/request-for-information-clinical-research-infrastructure-and-emergency-clinical-trials

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Articles

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

How Pharma Needs to Prepare for the Next Pandemic 

The coronavirus pandemic changed how clinical researchers view and treat data sharing. Previously it was a challenging proposition, because researchers want to make sure that they receive appropriate acknowledgement for their hard-won data. Now, with millions of lives at stake, the pandemic has prompted an urgent plea for the sharing and mining of existing clinical data and combining our resources. Most scientists now agree that data sharing is a moral obligation to save lives.

Last February, at the start of the pandemic, I wrote about how 

 means making urgent and swift changes to policy and infrastructure. In addition to encouraging data sharing, policy makers must change the current rules. One of the best examples of this was the 2003 SARS outbreak, which ushered in new protocols and increased disaster preparedness amongst healthcare leaders. It even changed the way new hospitals are designed and how patients are screened at triage stations.

Despite delayed policy changes, global forces are increasingly acknowledging the positive impacts of data-sharing and making strides to implement collaborative practices into ongoing trials. For example, the World Health Organization's (WHO) Solidarity PLUS trial, which represents the largest global collaboration among WHO Member States, will be sharing anonymized data after the trial completes. Solidarity PLUS is entering its second phase and will be testing four new therapies—artesunate, imatinib and infliximab—in hospitalized patients, to treat COVID-19.

The Solidarity PLUS trial is a global platform study which allows for the assessment of multiple treatments at the same time under a single protocol. By recruiting thousands of patients from all over the world, involving thousands of researchers in over 600 hospitals in 52 countries, this is one real-world example of how post-analysis data-sharing could help accelerate life-saving research.

Yet, this shift towards collaboration does not come without ethical, legal or operational considerations. How we share data and who we share it with is increasingly important—especially as the industry introduces more technologies to streamline data capture.

In the spirit of openness, below are the learnings gathered from working with our customers on 300+ COVID-19 studies in 40 countries across 1,750 hospitals. Below, I’ve outlined some best practices to follow:

6 best practices for successful data sharing in clinical research


Patients willing to participate in research are the driving force behind every clinical trial. By undergoing the inevitable burden of a clinical trial, they have earned the right to their own data. We should give trial participants the opportunity to own their trial data, and with that, the freedom to share it with other research projects. The only meaningful way to do that is through standardization of data (see next point).

Additionally, one of the few real use-cases of Blockchain-esque technology in clinical trials is to not only provide patients with a privacy preserving method, but also to track how their data has contributed to the global body of research. Wouldn’t it be amazing to be able to see that, as a trial participant, your decade old research data was used in over 15 scientific publications?


Standardizing data means using internationally recognized concepts like SNOMED or LOINC to annotate data, or in the very least, capture data in an agreed-upon data model so data from these projects can be pooled and analyzed in unison. Therefore, data is most valuable when it’s standardized. The goal is to assemble large amounts of accurate and usable data as quickly as possible. Taking a standardized approach should allow clinical data from around the world to be aggregated, which can accelerate the work of researchers, including large-scale clinical trials.


When collecting data from study participants, you must have the appropriate ethical and legal approvals. This means de-identifying the data. You’d be surprised how many COVID-19 data submissions have required major revisions because they contained personal information. Protecting the identity of individuals and healthcare information is a must, and this information needs to be de-identified.


Scientists and researchers dedicate their lives to furthering our understanding, and justly want credit for their efforts. For most scientists, seeing their name in a prestigious peer-reviewed medical journal is a career highlight and an acknowledgement of the hard work they and their team put in. So, give credit where credit is due. Acknowledge the scientists and researchers who gathered the data. 

 paper should acknowledge the people who actually generated the data, if you’re citing that dataset. Encourage data sharing by giving credit where it's due and acknowledging other people’s efforts.


This should come as no surprise. Building and developing partnerships are essential for successful data sharing. A number of partnerships between organizations and companies which would have never happened pre-pandemic were formed, focusing on finding a treatment for COVID-19. Forming a partnership provides not only financial and technical support but brings the parties closer together to facilitate data sharing, collection, and analysis.


Data openness cannot happen without transparent communication. As groups and organizations work together to share data, communication and trust is key. Due to the inherent uncertainty of the rapidly changing virus and global situation, tensions are high, and challenges may include breakdown in communication between different organizations. Having a regular meeting, with shared goals and vision will help to facilitate trust between partners and existing networks. There needs to be an alignment towards a shared vision, and honest and open communication is at the core of any successful partnership.

COVID-19 has forced scientists and researchers to change their views on data sharing. Now is the time to continue to advance scientific partnerships and research collaborations and shift the current industry mindset towards a data-sharing culture to maximize our effort to save human lives.

The priority is to save lives, not be acknowledged.

Derk Arts, MD, PhD

Articles

How Pharma Needs to Prepare for the Next Pandemic

What Can We Learn from Data-Sharing During the COVID-19 Pandemic?