Bayer’s Koenen: Decentralized Trials For Pivotal Studies Not 'Black Or White Scenario'
Executive Summary
A cross-section of biopharma experts including senior executives of Bayer, Boehringer Ingelheim and Accenture and US FDA Director at the India Office deliberate digitization and evolving trends in clinical research, including the potential of decentralized trials and metadata-driven automation.
High-profile industry experts and regulatory officials discussed, at a recent summit, a range of issues around trends in clinical trials including the role of digital technologies, metadata-driven automation and also real world data and predictive evidence in insight generation.
Addressing the annual summit of the Organization of Pharmaceutical Producers of India (OPPI), Dr Christoph Koenen, global head of clinical development and operations, Bayer AG indicated that clinical trials will remain a “cornerstone” of evidence generation of the future but with a shift to decentralized clinical trial (DCT) approaches.
“The whole idea of DCT as a concept is not going to change, but the technology you can use to successfully collect data in DCT is constantly going to evolve, and therefore going to change the pace of DCTs over the next coming years,” Koenen said at the virtual event.
Koenen also observed that while currently the acceptance of DCT-collected data for pivotal studies varies depending on “which regulator you talk to”, there is some skepticism around whether the data/end points collected using DCT has the same degree of quality as the traditional brick and mortar approach.
“That is the reason why you do not see right now completely DCT-run pivotal studies yet,” declared Koenen, who took charge in his role at Bayer in January this year moving from Otsuka Pharmaceutical Co. Ltd., where he held the position of Chief Medical Officer.
Regulators have, on their part, urged industry to talk to them or others with experience with DCTs, and ensure that such dialogue occurs early.
Not A 'Black Or White Scenario'
Nonetheless the Bayer executive believes that as industry’s experience and confidence with DCTs grow and evolve, their acceptance for pivotal studies will also increase.
“However, it might not be a black or white scenario where you will have a study that is done 100% brick and mortar and 100% DCT; we might find ourselves in a situation where we have a certain percentage of patients participating in the study by a DCT approach and then you might have certain percentage of patients that will participate in the study by a brick and mortar site,” Koenen explained.
The advantage of having this flexible approach, he said, is that you can make the participation in the DCT approach dependent on a specific patient's “living situation - how is the access to technology/data connection/home care - and you can take a very flexible approach.”
Earlier McKinsey & Co noted that the shift of trial activities closer to patients has been enabled by a constellation of evolving technologies and services including tools such as electronic consent, tele-healthcare, remote patient monitoring, and electronic clinical-outcome assessments which enable investigators to maintain links to trial participants without in-person visits.
The management consulting firm also indicated that the fully virtual model is gradually migrating from smaller, early-phase and post-approval studies towards larger pivotal trials.
“Nonetheless, in the near term, sponsors, investigators, and research-service providers expect fully virtual trials to remain limited to a narrow set of use cases, such as a well-characterized drug with few adverse events in a mild indication, with end points suited to remote measurement,” McKinsey executives said in a June 2021 article.
Digital Heath Technology - “Fit For Purpose”
Dr Sarah McMullen, director, US FDA India Office, touched upon aspects of leveraging different types of digital health technology (DHT) tools in the conduct of clinical trials.
McMullen urged sponsors to ensure that a DHT is “fit for purpose”.
“This can mean asking and answering questions such as is the tool reliable and appropriate to that context? Is the data to be captured valid to the intended research question? Is the consent process adequate for describing the risks of the use of this technology to the participant? And can it also be ensured for traceability from end-to-end usage and its main consideration for data integrity,” McMullen explained in the panel discussion at the OPPI summit.
In addition, the regulatory official also referred to cyber security risk, noting that most people have been probably impacted in some way in their lives by “some sort of cyber security risk or malfeasance in that area as well”.
In December last year the FDA had introduced a draft guidance “Digital Health Technologies for Remote Data Acquisition in Clinical Investigations” ; it provides recommendations to sponsors, investigators, and other stakeholders on the use of DHTs to acquire data remotely from participants in clinical investigations evaluating medical products.
The guidance suggests that sponsors should ensure that the level of validation associated with the DHT is sufficient to support its use and interpretability in the clinical investigation. (Also see "FDA Draft Guidance Paves Way For Collecting Clinical Study Data Via Digital Health Technologies" - Medtech Insight, 22 Dec, 2021.)
Kailash Swarna, managing director and global leader, clinical development, Accenture Life Sciences, who moderated a session on "Disruptions and Digitization Trends in Clinical Research" at the summit, highlighted how COVID-19 catalyzed systemic changes in clinical development and organizations have been forced to lean into virtual methods, leading to an increase in competency and investment in digital health.
On DCTs, he put forth that if industry could engender “confidence” in terms of using technology appropriately, "imagine what we could do in terms of bringing more patients into the clinical trial landscape". Ultimately the goal, he emphasized, is to make clinical development and clinical trials part of the continuum of care.
"So we actually see that from clinical trials to the practice of medicine there is continuity on how we can bring treatments to patients."
The clinical trials segment has been fraught with challenges such as low trial participation and recruitment, poor engagement and retention and high costs. Data from Accenture suggested that 86% of clinical trials do not meet enrollment timelines while 30% of participants identified do not complete the study on average.
Balance Between Digital Innovation And Disruption
Significantly, though, panelist Dr Vijay Prabhakar, head of therapeutic area, clinical development and operations at Boehringer Ingelheim, emphasized that not every patient potentially “likes” DCT and it is important to understand that the choice at the end of the day lies with the patient and the investigators.
“We shouldn't sometimes assume that anything digital is going to reduce complexity, because sometimes digital could also increase complexity. This is where at some point in time, we need to strike a balance between what we need as digital innovation versus being too disruptive that it becomes inconvenient for the patients and investigators,” Prabhakar said, among a string of other comments. Regulatory considerations pertaining to digital health technology were also part of the panel discussion (see side box).
The BI executive, though, sees a lot of untapped potential despite the pandemic, for instance "lot of future" in artificial intelligence speeding up adjudications, helping people adjudicate endpoints faster using radio mics. (Also see "Considerations For Using Established Versus Novel Endpoints In Decentralized Trials" - Pink Sheet, 18 Mar, 2022.)
“There are so many options that are still not being used,” said Prabhakar, a physician trained in intensive care and emergency medicine.
Clinical endpoint adjudication is a standardized process for assessment of safety and efficacy of pharmacologic or device therapies in clinical trials.
The McKinsey article referred to previously also highlighted the need to balance the needs of each stakeholder group in DCTs and provide them with a "positive, differentiated" experience. Patients, it noted, vary in their comfort with and access to technology and preferences for in-person physician visits versus visits by phone or video. “Patient-centric trial design is critical to mitigating such concerns. It can include, for example, patient training and support, user interfaces tailored to specific patient groups, and the option to choose between a decentralized arm and a conventional arm.”
Asundexian Program
Meanwhile Bayer’s Koenen also spotlighted the German group’s clinical trial approach for the investigational drug asundexian, where it is utilizing various innovative approaches.
Asundexian is an oral inhibitor of Factor XIa being developed as a potential treatment for secondary prevention in patients with a non-cardioembolic ischemic stroke as well as for atrial fibrillation and recent myocardial infarction.
The global head of clinical development and operations outlined how the program has a certain percentage of patients in the US where the DCT approach is used. “We have an agreement with global regulatory authorities that we can use some percentage of patients in this program - we collect the data using the DCT approach.”
The program has also used registries to identify patients that can potentially enter the study, therefore making sure that patients with the “right patient characteristic” are approached in order to be included in the trial, and “we do identify those patients in advance.” The German multinational is also automating processes of the study “as much as we can” in order to improve the quality as well as the speed that it takes to conduct the trial, he added.
Asundexian is currently being studied in the PACIFIC Phase II clinical trial program that consists of three Phase IIb studies in over 4,000 patients with one of the three medical conditions: atrial fibrillation, a recent non-cardioembolic ischemic stroke or a recent myocardial infarction. It is being studied in all three indications either as a standalone therapy, or in combination with anti-platelet therapy. (Also see "Xarelto Still Climbs As Bayer Touts Successor" - Scrip, 1 Mar, 2022.)
Metadata Driven Automation
Koenen, who has held senior leadership positions in clinical development at GlaxoSmithKline plc, Novo Nordisk, and Bristol Myers Squibb Company along his career journey, underscored the value of using metadata-driven automation to increase efficacy in how trial processes are run; currently these involve significant manual work which is time consuming and also "introduces quality risk."
“If we standardize it, automate this as much as we can and automate the generation of different documents, be it part of the protocol, be it part of the study report, then the quality of documents that we produce will improve and the time it takes to produce these documents will be much less,” he emphasized.
As technology evolves - artificial intelligence is expected to play a very important role – the ability to advance such efforts increase, he added.
Real World Data, Predictive Evidence
The Bayer executive also touched upon the growing importance of real world evidence, currently largely used to look at outcomes of different therapeutic approaches in a real world, mostly after drugs have been approved.
"What will happen is that the importance of real world evidence is going to increase and we will increasingly rely on real world evidence to make, for example, regulatory decisions around efficacy and safety as well."
He predicts that world is likely going to shift from a more traditional approach of using mostly trial evidence to make decisions to one that will use different kinds of evidence in order to make decisions. “In the future, real world data and predictive evidence [will] play an even more important role in the insight generation mix.”
Koenen, however, cautioned that such evidence can only be used if “we are sure that we are collecting, processing, analyzing and interpreting all these different kinds of evidence appropriately, and we have to make sure that we have the systems in place in order to do that.”
He also noted that with the use of digital technology in clinical trials alone, the volume of data industry is collecting is going to "explode" and referred to the example of home monitoring and having a patient wear three-lead ECGs (electrocardiograms).
“What if you have a patient wears this for a long, extended period of time? What if you start monitoring sleep, breathing pattern, pulse pressure in your clinical times and over a certain period of time.? Imagine the amount of data that you have to collect and store and process in order to do that.”
Hence, it’s important for industry to create advanced analytics and data ingestion platforms to handle that.
“So it’s our ability to store and collect data and then the ability to process the data, and then make sure that we analyze the data in an appropriate way to draw the right conclusions,” he added. With increasing volume of data, data handling capabilities need to be further strengthened, he underscored.