Applied Clinical Trials
Though the global pandemic that has affected millions, the industry has shown resilience and demonstrated a shared commitment to improving patient care.
It’s hard to believe that a global pandemic that has affected millions, and so far, taken the lives of hundreds of thousands could have any silver linings. After all, the loss of life alone is unfathomable in a time period where the majority believes that science, technology and medicine can protect us to a much higher degree than where we find ourselves today.
We have seen that the best solution to saving lives is based on a well understood epidemiological method that humans developed almost a century ago: quarantine. We have also seen how this draconian and necessary method has had a significant effect on businesses, especially those involving ongoing clinical trials, causing enormous hardships across the globe.
With this, we can observe unique disruptions to business processes which fall generally in three categories:
Clinical trials are a combination of these three models, but do not really fall within any one category.
To explore this further, let’s ask ourselves where the clinical trial enterprise falls. Let’s deconstruct this scenario as a play (as in Macbeth) that tells the tale of how a drug, biologic or device is born, tested and ultimately reaches the regulatory world on its way to market. In this play we have several actors; sponsors, CROs, KOLs, and agencies.
The conduct of the trial itself is mostly managed by CROs whose employees have for a very long time worked from home. These companies at the center of the script have for years had the basic technology allowing them to exchange ideas and information, mostly through email, video conferencing and good old telephone calls with their constituents including site coordinators, investigators, internal colleagues and KOLs. While not the most efficient, reliable or trackable, these methods have been at the core of clinical trials, and we all have learned to live with them. The global pandemic didn’t directly affect this part of the story.
There is however one actor in the play that we have not yet considered. In fact, it’s the protagonist, without whom there is no story: the subject. Clinical trial subjects are the reason the whole enterprise takes place. They are the source of all the answers regarding these grand experiments. Without subjects being physically available, there are no trials. Given that physical availability and quarantine are generally mutually exclusive, COVID has had a tremendous effect on the entire industry. Significant numbers of trial launches have been postponed, existing trials have slowed down appreciably, and sponsors and CROs found themselves in mostly uncharted territory. There were suddenly many obstacles preventing the most essential clinical trial management activities:
If finding naive subjects is one of the most expensive and difficult aspects of getting a trial going, not being able to interact physically with those subjects puts many studies and hundreds of millions of dollars of investments at risk.
As the pandemic continued and the stark reality of the current clinical landscape was revealed, many advocates urged for changes in the way we carry out these trials. The main buzzword making the rounds was Virtual Trials. Let’s explore at a high level what they are.
Virtual trials are generally understood to be the next generation of methodologies to enable the conduct of studies. These studies would increase the use of technology to provide subjects with the ability to participate without the current level of burden required to complete physical visits to investigator sites. These technologies include a variety of platforms and devices that enable remote processes such as wearable devices and video/telehealth. Use of these tools and methods will require certain changes in how subjects interact with those monitoring the study. Additionally, these trials would make greater use of data-mining processes to focus the investigations more specifically.
In principle, virtual trials are the natural evolution of our current processes. Consumer-level wearables, while in their relative infancy, will become more dependable with time. Once their reliability is such that regulatory agencies approve them for use just as they currently do with existing regulated devices like those used in cardiovascular or pulmonary studies, we will be closer to the virtual trial reality. Questions as to whether the devices are used properly and how that may affect results will be answered over time, and statistical analysis as well as AI-based result correlation will eventually convince us that the potential to introduce noise can be cancelled by an intelligent normalization algorithm or neural net.
However, there still remains the challenge of delivering therapies to subjects. Infusions and injections do not lend themselves to virtualization, which is why virtual trials also require decentralization. This component is interesting, in that it speaks to the need to enable subjects to minimize travel time to the facilities charged with delivering their therapies. This represents a distribution / supply chain problem in addition to important training requirements at remote centers. Presumably the current movement to decentralize hospital systems, by creating specialized satellite facilities, could accelerate this capability. The question remains whether and how decentralization can go beyond that without greatly increasing the cost and complexity of distributing supplies while also ensuring that subjects receive the right dosages of the right drugs, all at the right time.
Furthermore, there is something other than the physically constrained manner in which we conduct trials that needs attention. For the last 15 years we have developed capable systems to capture all the data necessary to determine whether the hypothesis set forth by the study is correct. Data capture systems abound and include EDC, CTMS, CDMS, IRT/RTSM, eCOA, ePRO, and eTMF among others. These form-based systems help ensure that data is correctly gathered and validated, and that it can be accessed either directly or through reports in many flexible ways. Some of this data validation is enhanced by the ability to implement validation workflows that guide users (whether trial professionals or subjects) as they go along by calculating their entries in real time and presenting different fields depending on earlier inputs.
COVID-19 has shown us that as we needed to adjust the way we worked in response to the pandemic, our processes didn’t necessarily have the level of flexibility or agility to be modified apace. It’s not that existing tools such as email and file sharing failed, or that existing systems could not be updated with additional fields. The challenge was that the type and level of collaboration required to manage the new and unexpected trial interactions and data flows were not codified:
COVID-19 has shown us that trial managers were doing everything possible to be helpful, but in the midst of the crisis, panic typically ensues. For instance, the industry had excellent data collection systems, but what was (and is!) lacking are process management capabilities: systems that can rapidly define the way in which people will collaborate to manage and determine how actions on data and between participants can move given processes forward. This challenge cannot be solved by a single, monolithic, all-encompassing system. The belief that the industry’s data capture and storage systems can be magically unified is fantasy.
As an industry we must think of ways in which collaborations can be codified to ensure that the data from all the various capture systems is made available at the proper time to the right individuals and in the appropriate context. These individuals will in turn add their analysis and pass it on to the next actor in the process, whether within or across corporate boundaries. Creating flexible people and system interaction tracks that can be laid and torn down on demand will allow us to be significantly more effective when the unexpected happens, while giving us both a roadmap and a history of our decision-making processes.
I believe that the post-pandemic clinical trial landscape will not be too different from the one we lived in at this time last year. The silver lining is the fact that our industry has shown resilience and demonstrated our shared commitment to improving patient care.
We are an industry firmly entrenched in Newton’s First Law: every clinical trial process persists in its state of rest or uniform motion in a straight line unless it’s compelled to change that state by forces impressed upon it. The COVID-19 pandemic has barely moved the needle. Even as regulatory agencies tried as best they could to relax certain requirements to enable the continuation of existing studies, the reluctance to change (and often take advantage of those relaxations) has been so ingrained in the industry that I believe opportunities were lost to prove that certain structural changes would not result in increased risk for subjects or their data.
Clinical trials will continue to move toward more virtualization and though we can expect a steady evolution, it will not be a revolution. In a world where we increase complexity by decentralizing (something I believe must happen!), where we rely more and more on AI-based retrospective analysis to guide our prospective decisions, and where we need to begin adopting supply-chain methods that elicit those of just-in-time manufacturing, the methods of collaboration between the actors in the clinical trial story must be vastly improved. Only when we can tell and trace every decision made at a moment’s notice will we have moved past an important inflection point that will change the conduct of clinical trials forever.
Abraham Gutman is the President & CEO of AG Mednet