Bridging the Gap Between RCTs and RWE Through Endpoint Selection

LoCasale, Robert; Pashos, Chris L.; Gutierrez, Ben; Dreyer, Nancy A; Collins, Toby; Calleja, Alan; Seewald, Michael; Plumb, Jonathan; Liwing, Johan; Tepie, Maurille Feudjo; Khosla, Sajan

doi:10.1007/s43441-020-00193-5

Cited by 11 publications

(9 citation statements)

References 16 publications

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“…Business motivations may also play a role in endpoint selection, including the desire to minimize price competition by differentiating products from those of competitors. 41,42 The use of separate endpoints can make direct comparisons challenging even if products would perform similarly when tested using the same endpoint. The use of different endpoints can also be leveraged to imply an advantage over a competitor, even if the advantage has not been established in a head-to-head trial.…”

Section: Discussionmentioning

confidence: 99%

Variation in Endpoints in FDA Medication Approvals

Sharpless,

Kesselheim,

Orr

et al. 2023

Neurology

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Background and Objective:To assess the characteristics and extent of variation of the endpoints used in trials supporting FDA approval of medications treating migraine.Methods:Using the Drugs@FDA online database, we identified novel prescription medications approved by the FDA between January 2001 and September 2022, for migraine with or without aura, for both acute and preventive treatment, and for episodic and chronic presentations. For each medication, we used the most recent FDA-approved labeling to identify indication, mechanism of action, mode of administration, manufacturer, approval year, number of pivotal trials, trial design, and primary endpoints.Results:Sixteen FDA-approved medications for the acute or preventive treatment of migraine were supported by 45 pivotal trials. There were 5 primary endpoint types: 1) Change in Mean Monthly Migraine Days from Baseline; 2) Change in Mean Monthly Migraine Attacks from Baseline; 3) Change in Mean Monthly Headache Days from Baseline; 4) Mild to No Pain After 2 Hours; 5) Pain-Free at 2 Hours. There were 3 combinations of co-primary endpoints: 1) Headache Pain Free at 2 HoursandMost Bothersome Symptom Free at 2 Hours; 2) Pain-Free at2HoursandSustained Pain-Free from 2-24 Hours Post-dose; 3) Pain-Free at 2 Hoursand2-24 Hours Sustained Pain Freeand2-Hour Pain Relief. Of the 8 preventive migraine medications, the timing of endpoint measurement included the full double-blind period, segments of the double-blind period, and the final month of the double-blind period.Discussion:Migraine medication trial endpoints were inconsistent within the same indication (episodic or chronic), mechanistic class, and route of administration, frustrating direct comparison among these medications. Further, inconsistent definitions for the indications “episodic” and “chronic” migraine were also observed. Consistent endpoint selection for medications approved for preventive and acute migraine treatment would enhance the ability of patients, physicians, and payers to make informed choices among these medications.

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Section: Discussionmentioning

confidence: 99%

Variation in Endpoints in FDA Medication Approvals

Sharpless,

Kesselheim,

Orr

et al. 2023

Neurology

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“…Changing regulation, policy, and healthcare delivery have created increased pressure for R&D companies to deliver assets faster, often for competitive indications that have multiple existing therapies. 10 While RWE often cannot supplant "gold standard" RCTs, 47 it can nonetheless provide insights needed to streamline RCTs to reduce their duration and costs. [48][49][50] Although clinical trials are complex and can fail for many reasons, uncertainty at the design stage (e.g., optimal sample size, endpoints, follow-up) is an important contributing factor.…”

Section: Use Of Rwd To Inform Clinical Development Informing Trial Designmentioning

confidence: 99%

“…However, the endpoints favored by one stakeholder (e.g., regulatory agencies) may not always be meaningful to other stakeholders (e.g., patients, payers, and HCPs). 10 This misalignment is particularly challenging with biopharmaceutical products that receive accelerated regulatory approval based on changes in surrogate endpoints (e.g., biomarkers). Additional studies are then required to confirm the clinical benefits of these changes; such "confirmatory" studies increasingly involve novel clinical trial designs (e.g., pragmatic trials) that incorporate RWE.…”

Section: Selection Of Endpoints and Identification Of Surrogate Endpointsmentioning

confidence: 99%

“…Although key stakeholders, such as biopharmaceutical companies, regulators, payers, health technology assessment agencies, patient advocates, and policy makers, generally agree on the limitations of RCTs (e.g., insufficient follow-up duration, use of surrogate endpoints, and smaller sample sizes), they have yet to reach consensus on the optimal use of RWE. [4][5][6][7][8][9][10][11] Because much of the recent RWE literature has focused on regulatory aspects (e.g., approval of new products for rare diseases based on single-arm trials with external control arms) 6,11,12 , this paper will instead focus on the value of RWE to guide the research and development (R&D) process within biopharmaceutical companies. 13 The following topics will be discussed: (1) use of RWD to guide pipeline and portfolio strategy; (2) use of novel sources of RWD to inform product development; (3) use of RWD to inform clinical development; (4) advanced analytics and tokenization to harness "big" RWD; and (5) considerations when using RWD to inform internal decisions.…”

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confidence: 99%

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Use of Real‐World Evidence to Drive Drug Development Strategy and Inform Clinical Trial Design

Dagenais

Russo

Madsen

et al. 2021

Clin Pharma and Therapeutics

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Interest in real-world data (RWD) and real-world evidence (RWE) to expedite and enrich the development of new biopharmaceutical products has proliferated in recent years, spurred by the 21st Century Cures Act in the United States and similar policy efforts in other countries, willingness by regulators to consider RWE in their decisions, demands from third-party payers, and growing concerns about the limitations of traditional clinical trials. Although much of the recent literature on RWE has focused on potential regulatory uses (e.g., product approvals in oncology or rare diseases based on single-arm trials with external control arms), this article reviews how biopharmaceutical companies can leverage RWE to inform internal decisions made throughout the product development process. Specifically, this article will review use of RWD to guide pipeline and portfolio strategy; use of novel sources of RWD to inform product development, use of RWD to inform clinical development, use of advanced analytics to harness "big" RWD, and considerations when using RWD to inform internal decisions. Topics discussed will include the use of molecular, clinicogenomic, medical imaging, radiomic, and patient-derived xenograft data to augment traditional sources of RWE, the use of RWD to inform clinical trial eligibility criteria, enrich trial population based on predicted response, select endpoints, estimate sample size, understand disease progression, and enhance diversity of participants, the growing use of data tokenization and advanced analytical techniques based on artificial intelligence in RWE, as well as the importance of data quality and methodological transparency in RWE.

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“…Real-world data come from a variety of sources, such as electronic health records, insurance claims and billing databases, patient registries, patient health records (observation charts, abstraction, laboratory, and pharmacy data), patient surveys, and digital health devices, such as wearables, mobile applications, and social media [7,[11][12][13]. Real-world data when analyzed provide valuable RWE and insights that can be leveraged to achieve a number of benefits in real-world scenarios, such as a clear picture on the outcomes with new therapies and the estimation and quality upgrade of new targets and interventions [13][14][15]. Real-world evidence further helps to approve improved methods of patient care and enhance health technology assessments, which have effects on market access and financial gains [16][17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Promise of Real-World Evidence for Patient Centricity in Gulf Cooperation Council Countries: Call to Action

Farghaly

Ghaithi

Mahamid³

et al. 2022

Drugs - Real World Outcomes

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Presently, Gulf Cooperation Council countries are lagging in the generation of real-world data and use of real-world evidence for patient-centered care compared with the global average. In a collaborative effort, experts from multiple domains of the healthcare environment from the Gulf Cooperation Council countries came together to present their views and recommended key action points for the generation of robust real-world data and leveraging real-world evidence in the countries. The opinions of the experts are presented, along with existing barriers to the effective generation of real-world evidence in the countries. The Gulf Cooperation Council countries are undergoing transformative changes paving the way for improved healthcare measures; however, the challenges in generating reliable, robust, accessible, and secure real-world evidence are persistent. Hence, ongoing public-private engagements, as well as collaborations between regulators, policymakers, healthcare professionals, insurance and pharmaceutical companies, and patients, are warranted. A few notable examples of real-world evidence studies highlighting the benefits of real-world evidence for gaining valuable insights into patient-centric decision making are also discussed. The actionable steps identified for successful real-world evidence generation would provide long-term, real-world evidence-based patient-centric benefits for the countries.

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Bridging the Gap Between RCTs and RWE Through Endpoint Selection

Cited by 11 publications

References 16 publications

Variation in Endpoints in FDA Medication Approvals

Variation in Endpoints in FDA Medication Approvals

Use of Real‐World Evidence to Drive Drug Development Strategy and Inform Clinical Trial Design

Promise of Real-World Evidence for Patient Centricity in Gulf Cooperation Council Countries: Call to Action

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