Archive for category RWE

Advancing Real-World Evidence with Pragmatic Clinical Trials: Interview with Dr. Joseph Singer, Chief Medical Officer of HealthCore-NERI

Dr. Patti Peeples, CEO of HealthEconomics.Com, sat down with Dr. Joseph Singer, CMO of HealthCore-NERI, to discuss how pragmatic clinical trials are advancing real-world evidence (RWE). The mission of HealthCore-NERI is to provide clarity that empowers decision makers to act with precision to improve quality, safety, and affordability in healthcare. HealthCore-NERI works with life science companies, payers and providers, and government and academic organizations to provide real-world evidence in support of a wide variety of healthcare decisions.


Dr. Peeples: What is the shift we are seeing in the industry from typical Randomized Controlled Trials (RCTs) design to Pragmatic Clinical Trials (PCTs) design?

Dr. Singer: For the past fifty years, healthcare has been relying on randomized controlled trials (RCTs) to establish safety and efficacy of medical and surgical treatments. RCTs have been integral in establishing the potential efficacy and the beginning of understanding the risk profiles of new treatments and interventions.  While RCTs have been the standard for evaluating early phase therapies, they are limited in evaluating treatment options in a real-world, post-approval setting.  Real-world evidence using pragmatic clinical trials (PCTs) is increasingly being used for decision making by payers, life science companies, health systems, and practicing physicians. There is a need for devices and interventions, both biopharmaceutical and surgical, in a value-based system to demonstrate the actual benefit and risks occurring in a real-world patient setting, as opposed to the tightly controlled populations of a traditional RCT. Pragmatic studies allow for observation of a more generalizable and diverse population, and are designed to include many different kinds of patients – with various comorbidities, ages, and demographics. We have seen a strong industry shift toward these new types of studies with the PDUFA VI Regulations and the 21st Century Cures Act, requiring the FDA to explore the use of real-world evidence in support of new indications for approved drugs or fulfill post-approval requirements. There is significant potential gain by integrating results of both efficacy from RCTs and effectiveness from PCTs to personalize most appropriate placement of an intervention in the treatment plan of individuals by their treating physicians.

Dr. Peeples: How are Pragmatic Clinical Trials advancing Real World Evidence?

Dr. Singer: Currently, as little as 15 percent of clinical guidelines are based on solid evidence.  For instance, if we zero in on cardiovascular guidelines, there are 16 high impact cardiovascular guidelines used to power healthcare decisions by payers, healthcare providers and consumers – with 2,722 recommendations within these guidelines. However, only 11 percent are actually based on enough evidence to warrant the recommendation, with most only relying on a single trial or expert opinion.[1] Expert opinion is essential to fill gaps in evidence when strong scientific evidence has not been generated, but it is not optimal for personalizing care for any given patient.

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One way to get at generating real-world evidence is through retrospective research looking at utilization and costs, but another important way to study real-world evidence is through prospective study designs that randomize patients to various treatment options to determine the appropriate treatment for patients in the real world.  PCTs enable the healthcare industry to more nimbly and efficiently answer questions related to how a treatment option performs in a real-world setting, contributing important evidence to establish future clinical guidelines that are applicable to a broad array of patients.

Dr. Peeples: What are the benefits to Pragmatic Clinical Trial design?

Dr. Singer: While retrospective research can answer important questions about trends and utilization of certain treatment options, prospective study designs allow us to more accurately observe treatment effects because of randomization.  However, traditional prospective study designs, such as RCTs, offer challenges in terms of implementation and often don’t include a representative patient population.We know that over90 percent of patients do not participate in traditional RCT research.  An important contributing factor is the overall burden, time and resources required of participating physicians and patients in these complex and highly structured studies. Because pragmatic clinical trials are rooted in real-world practice, they require significantly less time and resources. Physicians do not need to take hours on a daily basis to document findings, to hire additional staff and disrupt their typical practice operational flow. Often times, patients’ participation in the trial only requires informed consent, randomization and responding to a few surveys. Therefore, it opens the door to include many more physicians for participation and offers opportunities for their patients, which ultimately improves our understanding of how treatments perform in routine practice.

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PCTs are designed to be minimally burdensome to both participating physicians and patients, are structured to allow existing office staff to do much of the work, and minimize the bureaucracy and paperwork associated with performing research.

Dr. Peeples: What are some of the challenges with implementing PCTs?

Dr. Singer: Moving from high-touch research interventions to real-world pragmatic studies requires a complete shift in mindset among the FDA, the industry, trial sponsors and trial participants. What works in RCT implementation may not work in PCT implementation. Rather than targeting the same traditional physician groups, who offer a limited number of patients, there is an opportunity to work with more research limited or research naïve sites.  Working with these sites does pose some challenges, such as provider and patient unfamiliarity with research and limited staff support and resources. However, the lean resource approach PCTs can take allows seamless integration with community clinics who may lack experience with research but who have the ideal patient population for implementation.

Dr. Peeples: How can we overcome barriers to physician and patient recruitment?

Dr. Singer: We recognize that85 percent of RCTs fail to meet recruitment targets, with 15 to 20 percent of trial sites never enrolling a single patient.[2,3] To meet and exceed targets and timelines, a new set of tools is needed to address physician and patient recruitment into PCTs. First, it is essential to know the ideal physicians and sites to target and approach. Secondly, sites need the appropriate tools and resources to identify and enroll patients, and conduct the research. Through the use of site intelligence (physician and patient population demographics), targeted physician and patient communications, and technology automation, PCTs can improve efficiency, meet enrollment targets and exceed timelines.

Dr. Peeples: What is the best way to get started on designing and implementing a PCT?

Dr. Singer: Success for PCTs involves an understanding of the unique challenges of pragmatic studies, and having the right tools to overcome those barriers. At HealthCore-NERI, through the Integrated Research Network (IRN), a connected network of physicians, integrated delivery systems, patients and payers, we are building the ecosystem to support real-world evidence, pragmatic clinical trials. The IRN uses a unique identification and automation processor to leverage existing relationships and intelligence collected on sites to accelerate time to first patient in. Through targeted communications, we equip sites with the tools they need to be successful in patient recruitment. We’ve created a community where physicians and patients become the direct recipients of the research we conduct to improve quality and satisfaction and to foster long-term engagement.

Dr. Peeples: Thank you, Joe. For more information on the Integrated Research Network (IRN), pragmatic clinical trials, and other HealthCore-NERI research solutions, contact IRN@HealthCore.com.


[1] Tricoci P, Allen JM, Kramer JM, Califf RM, Smith SC Jr. Scientific evidence underlying the ACC/AHA clinical practice guidelines. JAMA. 2009; 301:831–41. Available here: https://jamanetwork.com/journals/jama/fullarticle/183453

[2] Carlisle B, Kimmelman J, Ramsay T, MacKinnon N. Unsuccessful trial accrual and human subjects protections: an empirical analysis of recently closed trials. Clin Trials 2015; 12:77-83. Available here: https://journals.sagepub.com/doi/abs/10.1177/1740774514558307?journalCode=ctja

[3] Budgeting at the Investigative Site, University of North Carolina at Chapel Hill, Office of Clinical Trials Newsletter. July/August 2006.

Dr. Joseph Singer is responsible for guiding HealthCore-NERI’s project teams to optimize the clinical, coding, and insurance industry perspectives embedded within their analytic projects. He also supports development of clinical aspects of HealthCore-NERI’s research environment and manages HealthCore-NERI’s Integrated Research Network (IRN). As an Initiative Owner, he is leading the development of a research environment to optimize the efficiency and effectiveness of studies performed by HealthCore-NERI. He serves as clinical lead for several Payment Innovation activities within Anthem, Inc. (i.e. building the bundled payment methodologies), as well as provides leadership in numerous enterprise steering committees

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Artificial Intelligence for Real-World Evidence

Costas Boussios, VP of Data Science, OM1
Richard Gliklich, CEO, OM1

As artificial intelligence (AI) and Big Data are lauded for their potential uses in life sciences and healthcare, it is becoming difficult to differentiate between the myriad of terms and technologies and their real value in advancing real-world evidence (RWE).   In this article, we explore key AI and Big Data terms, their real-world application, and how they are building upon each other to transform our understanding of patient journeys and outcomes.

Big Data

Although Big Data is not required for artificial intelligence, much of the utility of AI comes from its application to large sets of information in the development of real world evidence.  The term Big Data reportedly was first used by NASA engineers in the 1980’s who were trying to work with datasets that exceeded their ability to store and analyze them with traditional computing software. Since then, the emergence of the world wide web and the development of advanced computing machinery and software applications has resulted in an explosion of data-generating applications. Today, Big Data is bigger and more ubiquitous than ever before.

The need to store, secure, query, process, analyze and manage Big Data has led to the development of numerous technological innovations over the last 20 years. Earlier proprietary solutions, such as the Google Distributed Filesystem, have been succeeded by widely available open-source technologies, such as Apache Hadoop.

Furthermore, Cloud Computing solutions such as Amazon Web Services, Microsoft Azure and Google Cloud provide flexible, on-demand computing capabilities with the potential of minimizing IT capital and maintenance expenses for organizations of any size. The availability of free or flexible cost capabilities, thanks to the open-source community and to Cloud computing platforms as described above, have resulted in enhanced democratization of Big Data capabilities across industry sectors and budgets.

From a real-world evidence perspective, one of the main advantages of Big Data infrastructure is the ability to maintain very large, heterogeneous and linked data sets that are highly available, where they can be queried and statistically processed rapidly and can be used in visualizations on a near real-time basis.  For example, not only can data be updated and added to existing visualizations such as for tracking the opioid epidemic on a real-time basis across the entire U.S., but even extremely large custom cohort studies, such as answering questions on lipid lowering therapy or type 2 diabetes, representing millions of people and billions of data points, can be accomplished in hours or days rather than months or years (if data needs to be collected).  In addition, important AI implementations have been made easier thanks to increased integration of AI algorithms with Big Data software.

Natural Language Processing (NLP)

Natural language processing (NLP) is an AI tool that can be described as the ability of a computer program to understand the human language and automatically extract contextual meaning. NLP can be particularly useful in processing and evaluating large amounts of unstructured data. In healthcare, a common application is to evaluate physician notes in patient medical records, and find relevant information. By applying NLP, a system can more easily and rapidly extract and analyze data that would otherwise be too burdensome for researchers. NLP replaces the highly cumbersome act of medical chart extraction using teams of researchers.

NLP Techniques range from simple word-based models for text classification to rich, structured models for syntactic parsing, collocation finding, word sense disambiguation, and machine translation.

The NLP demand for real-world evidence is highly driven by the tremendous increase in textual unstructured clinical data. The practice patterns used by physicians for the documentation of clinical notes as well as patient discharge summaries have generated an enormous amount of unstructured data. Such voluminous data needs to be structured and analyzed effectively for enhanced reporting and analytics.  NLP, combined with machine learning and deep learning as described below, is rapidly becoming accurate enough to automate or replace abstraction.  This drives significant efficiencies in generating information from text for real world evidence purposes.

For example, NLP can be applied to find information on treatment outcomes, adverse events, symptom presentation and referral patterns. Consider the following physician notes examples:

“He states the symptoms are controlled. Less than 1% BSA currently affected.

Stopped [Drug X] d/c ‘increased depression.’ On Paxil but “feels not helping.” No psoriasis flares.”

“She has psoriasis on the back of her legs, torso, scalp.  She uses a dermatologist.  She was off [Drug X] for a URI and flared up.

The underlined information are just examples of what is not captured in either billing or structured EMR data.  The ‘old way’ would be to use nurse abstractors to chart review a small sample of patients.  With advanced NLP, data on such things as reasons for discontinuation of a medication can now be captured at scale across tens of thousands of patients for less than the cost of a traditional chart review.

Machine Learning, Deep Learning and Cognitive Computing

Machine Learning (ML) is a library of algorithms that scour over large volumes of data to accurately and efficiently learn relationships found in recorded examples. Over the last 15-20 years, ML has gradually been replacing traditional statistical inference as the tool of choice for learning complex relationships in data. The key advantage of ML is the capability to operate on large numbers of engineered predictive features in datasets including outliers, noise and collinearities, without the stability and reliability concerns of traditional statistical modeling. One of our key applications of this capability has been in identifying patients with undiagnosed or underdiagnosed conditions.  For example, the current approach is to use coded billing information or prescriptions to identify patients.  Using ML, we are able to see much more complex patterns and interactions that are similar between patients with and without a particular diagnosis and able to confirm that the diagnosis is present but either unlabeled (such as in dementia) or unrecognized (such as in early presentation of rare diseases like muscular dystrophy).  This technology has the promise of improving diagnosis in the clinic as well as in research studies.

Deep learning is a newer generation of learning algorithms rooted in an older concept called neural networks.  Neural networks use an array of nodes to perform computations or decisions rapidly.  Deep learning can be thought of as stacking many neural networks. Deep learning has introduced the capability to effectively automate the generation of predictive features in various types of inference problems and thereby achieve breakthrough performance in applications such as image processing, speech recognition and language translation.  In healthcare, some of the key applications of deep learning that are being pursued are for reading radiology exams or pathology slides.

Predictive vs Prescriptive Analytics

One of the most intriguing and potentially game changing examples of machine learning is in the area of predictive and prescriptive analytics.  With traditional research approaches, evidence development focuses on evaluating and tracking what has already happened. But, how do we move from understanding what happened to being able to predict what will happen 6 months, a year, 5 years out?

Using different mathematical techniques and modeling, predictive analytics use existing data to find trends and patterns and tell us what might happen. They help to identify who is most at risk and what outcomes can be expected.

Traditionally, risk analytics have been performed using standard statistical techniques such as stepwise logistic regression. In these approaches, characteristics or risks are identified and added into models to determine their impact on the model performance.  While predictive analytics can be generated using traditional statistical approaches, ML enables models to be generated to include thousands of variables and millions of data points.  The result is usually more highly performant models as well as the ability to uncover more data relationships of importance that might not have been considered to be so prior to the analysis.

For example, we recently presented a machine learning based model for predicting heart failure readmissions that outperformed existing models (LACE Risk Score) by 10 points[1] and relied on another machine learning based variable that measures the aggregate disease burden of a patient (OM1 Medical Burden Index (OMBI™)[2] and which is the strongest single predictor of many outcomes (heart failure admission and readmission, resource utilization).

Prescriptive analytics are an advanced form of predictive analytics. The goal of prescriptive analytics is to make the information presented actionable to a decision maker. Prescriptive analytics tell us what to do about the information that the predictive models generated and help us to know which ones matter most and what actions to take. For example, a clinician might use predictive analytics to understand who is most at risk for a cardiac event, whereas prescriptive analytics might tell the provider which patients have alterable factors, such as weight loss or smoking status, and which ones will have the greatest impact on outcomes.

As one can imagine, the healthcare and real-world evidence applications of these AI driven capabilities are potentially enormous.  Clinicians are already using these capabilities to identify which patients are most likely to have poor clinical or financial outcomes and to proactively take actions to minimize that risk.   For example, avoiding a cardiac readmission can save a health care payer or at-risk provider $14,000-$18,000 on average per event.  The implications are similarly large for manufacturers.  Predictive analytics are now being applied to identify patients most likely to benefit from certain treatments, those likely to be adherent to therapy, or even those likely to suffer an adverse event.

Conclusion

Artificial intelligence and big data are transforming real-world evidence from a largely retrospective viewpoint to a more concurrent and forward-looking set of capabilities.  This paradigm shift also will drive RWE to the forefront of strategy for both healthcare and life sciences organizations.   While there are many different components of AI that offer new approaches and methods to evaluating and generating real-world evidence, one common thread throughout is the importance of big data and the interdependency on having access to enormous amounts of data.

By embracing the innovation in AI (and the availability of big data), researchers can generate real-world evidence that is more dynamic, timely, representative, comprehensive and cost-effective.  This next generation of real-world evidence will also have the ability to be used to measure, predict and personalize care in a way previously not possible. In the end, all healthcare stakeholders benefit when medical products and services are focused on and delivered to those who will benefit the most.


[1] Su Z , Brecht T , O’Donovan F , Boussios C , Menon V , Gliklich R , Fonarow GC. Machine Learning Enhanced Predictions of Hospital Readmission or Death in Heart Failure. AHA Scientific Sessions. November 11-15, 2017. Anaheim, CA.

[2] O’Donovan F, Brecht T, Kekeh C, Su Z, Boussios C, Menon V, Gliklich R, Fonarow G, Geffen D. Machine Learning Generated Risk Model to Predict Unplanned Hospital Admission in Heart Failure. AHA Scientific Sessions. November 11-15, 2017. Anaheim, CA.

 






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