Recent breakthroughs in our understanding of the molecular and genetic underpinnings of cancer have revolutionized oncology care. From immune checkpoint inhibitors to CAR T-cell therapies and personalized medicine, physicians today are able to offer more effective and much less toxic options to millions of patients. But the clinical research industry is straining to keep up. The increasing complexity of clinical trial protocols, growing burden on participating sites and patients, and escalating costs of regulatory compliance, data monitoring, and trial infrastructure threaten to slow the development of new tools for cancer diagnosis and treatment.
Prospective real-world studies (PrwS) are emerging as effective supplements to the evidence generated by randomized controlled trials (RCT) for a range of critical use cases, from postmarketing to discovery and safety studies. Embedded into the standard clinical workflow, they can help biopharma companies answer important research questions conclusively without the burden and complexity of a traditional clinical trial, and without many of the limitations associated with retrospective studies.
Let's examine how prospective real-world studies thread the needle, and learn how you can integrate them seamlessly into your clinical research portfolio to fill gaps in your evidence generation capabilities.
PrwS vs. randomized clinical trials
While randomized clinical trials (RCTs) remain the gold standard in medical research, they can take a long time to execute. To assess causality and minimize confounding variables, RCTs tend to impose very strict inclusion/exclusion (IE) criteria — making patient enrollment complex and time-consuming. The burden to participate is often too high for patients, their clinicians, and the clinical sites targeted by the study, leading to poor adherence, retention and costly protocol amendments. There’s also increasing recognition in the research community that results from experiments done in specialized, highly controlled research settings lack representativeness and may not be uniformly generalizable to real-world practice.
Prospective real-world studies, on the other hand, can be designed to use the types of pragmatic approaches advocated by the FDA in Project Pragmatica: “broader eligibility criteria, ease of recruitment and follow-up, flexibility in delivery of the intervention, and use of more patient-centric outcomes.” They can be embedded into the standard clinical workflow and capitalize on recent advances in electronic health record (EHR) adoption and much-improved electronic data capture (EDC) technology at the point of care.
In the FDA’s own words, those design principles can benefit researchers “across a range of clinical and regulatory contexts while maintaining patient safety and data integrity.”
PrwS vs. retrospective real-world data studies
How do prospective real-world studies compare to retrospective real-world data studies?
Retrospective real-world data (RWD) is a fantastic asset for clinical research. Its scale can be enormous, covering a rich variety of diseases, patient profiles, clinical settings and treatment options, and its longitudinal quality makes it possible to study outcomes at every step of the patient journey. There’s no wait time either — the data has already been collected.
But as Flatiron’s Vice President of Research Oncology Dr. Neal Meropol pointed out in a recent interview, “There are questions that retrospective, off-the-shelf data can't answer because the baseline characteristics are not fully documented during routine care to allow researchers to build a cohort of interest, or because the outcome measurements are not applied consistently enough for regulators to interpret the results.”
Missing data can be a big challenge for retrospective RWD studies because missingness is rarely random, and most approaches to fill the gaps or discard incomplete records have the potential to introduce bias and confound the results. But prospective real-world studies can be designed to address questions of data missingness head on and capture critical new data that isn’t typically collected during routine clinical care.
What are some of the most promising use cases?
Early promising use cases for PrwS
Thanks to technological advances and guidance from the FDA, Reagan Udall and others, biopharma companies and sponsors are starting to realize that prospective real-world studies are not just technically feasible, but that they can also dramatically streamline their clinical trial operations and help them fulfill rigorous regulatory obligations.
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Post-marketing |
A natural application domain for PrwS has been in the area of postmarketing commitments and requirements (PMC/PMR), a costly part of the drug development process and a vital step for biopharma companies to meet regulatory requirements for drugs already on the market. Recently, Flatiron Health helped a large pharma company weigh the pros and cons of a pragmatic prospective study against a traditionally designed Phase IV study to assess risk factors for a multiple myeloma treatment. The prospective design accelerated site activation and simplified patient enrollment and improved patient representativeness, with the study enrolling nearly six times faster than traditional postmarketing study approaches and at an estimated 20-30% cost saving. |
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Discovery |
Post-approval trials aren’t the only candidates for PrwS. Genentech, Flatiron Health and Foundation Medicine (FMI) ran the Prospective Clinico-Genomic (PCG) Study in 2021-23 to discover the extent to which ctDNA changes might complement real-world response in assessing outcomes for patients with advanced lung cancer. The study not only established that there was an association — ctDNA increase was associated with higher risk for progression — but also exceeded operational objectives by streamlining all data capture and by recruiting 950 patients at the peak of the pandemic, with some sites enrolling over 40% of their eligible patient population. |
The examples above are only scratching the surface of what can be done with PrwS, but they show what difference prospective evidence generation can make at every stage of the drug development and commercialization cycle, and how receptive the FDA and other regulatory agencies can be when those studies are well designed.
Towards operationalizing prospective real-world studies
While prospective real-world studies are less complex than traditional clinical trials, they still require careful planning to capture data that’s relevant to the research question and capable of supporting regulatory submission. Sponsors don’t want to reinvent the wheel with every study. Thankfully, they don’t have to.
For example, at Flatiron, we’ve assembled a large network of 100+ research sites, the Flatiron Research Network (FRN), and equipped those sites with all the necessary trial management and integrated point-of-care technology to run prospective studies without disrupting routine clinical care. We’ve developed a dedicated prospective evidence generation platform to allow sponsors to run studies in the FRN under a master platform protocol, greatly simplifying study administration and management. While the platform establishes the operational infrastructure and regulatory framework for data collection, new studies — with their own specific objectives, eligibility criteria, patient consent, schedule of activities and data collection — can be easily embedded without the need to stand up new infrastructure.
With access to a robust platform on a broad integrated network of real-world clinical sites, sponsors can run prospective real-world studies much more efficiently and start generating critical evidence faster.
Benefits for the whole system
In discussing the implementation of an effective post-market pragmatic evidence generation framework, the Reagan-Udall Foundation noted that it should be grounded in the expectation that “all components of the healthcare ecosystem have an obligation to generate new knowledge that improves clinical care or public health and will benefit the whole system by doing so. As such, all participants in healthcare delivery should be encouraged to be engaged in pragmatic evidence generation either by provision of funding, research infrastructure or by participating as providers.”
The PCG Study mentioned earlier involved 24 different sites, and 100% of them indicated a willingness to take on similar trials again because the study helped advance clinical knowledge and, in Reagan-Udall’s words, ‘benefited the whole system’ without adding any strain to their point-of-care operations. “All of the clinical data in the PCG Study was captured directly in the EHR, processed entirely remotely and linked to the genomic data — all with very minimal site intervention,” noted Flatiron Head of Prospective Studies, Clinical Solutions, Josh Buddle in a recent webinar on modern RWD applications. We’re constantly adding more sites to the FRN through strategic partnerships with market leaders like ACCC and NCCN, and we’re encouraged to see that our current efforts to operationalize prospective evidence generation are helping raise the profile of prospective real-world studies among all stakeholders.
For more details on prospective real-world studies, check out this recent webinar with clinical operations and regulatory experts from Flatiron Health, Exact Sciences, and John Hopkins University. You can also read here about our partnership with Exact Sciences to run a multi-year prospective clinical study evaluating a tumor-informed test for monitoring cancer recurrence across multiple solid tumor types.
To learn more about how your organization’s clinical trials can benefit from a prospective real-world study platform, contact the Flatiron Clinical Research team.
