Regulatory Submissions Research Articles

Establishing a core dossier for multiple regulatory submissions: a case study in the Latin America region.

The Latin America region comprises several countries that do not follow harmonized regulatory requirements for drug product (DP) marketing authorization applications (MAA), resulting in customized registration dossiers for each country. Here, we established a core dossier for multiple MAA in the Latin America region by examining the similarities between regulatory requirements and reconciling their potential discrepancies through discussions among all national regulatory representatives. The core dossier was used in the submission of a new small molecule, NME1, to nine markets. Assessment of the process included the time to submission; the timing, number, and complexity of questions received; and timing of final national regulatory agencies (NRA) evaluation decisions. The core dossier resulted in an accelerated submission timeline for most markets and earlier receipt of NRA queries from some markets, compared with projections. One round of queries of a low or medium complexity was received from all agencies. The receipt of final NRA evaluation decisions was also accelerated in most markets, compared with the best-case approval timeframes. The core dossier approach was also evaluated against the standard submission of a similar small molecule, NME2. In contrast to the core dossier submission of NME1, a second round of questions, and high-complexity questions were received from two markets for NME2. In conclusion, a core dossier has the potential to simplify the regulatory process for both reviewers and applicants in regions that do not share harmonized regulatory requirements, with a consequential acceleration of DP approvals.

CDISC Enables Efficient Streamlining of Clinical Trial Safety Evaluation

The use of standardized data formats has increasingly facilitated both the submission of clinical trial data by pharmaceutical companies and its review by regulatory agencies. The Clinical Data Interchange Standards Consortium (CDISC) format has become the de facto worldwide standard for clinical trial data submissions and review. CDISC data are captured and organized in defined datasets, or domains, with predefined variable names and attributes. As a result, researchers and reviewers have a consistent, repeatable, and rapid way to load, review, and analyze data. The benefits provided by this standardization have culminated in the development of software that intuitively utilizes CDISC structures to quickly import and analyze the data as well as summarize the results for scientists and clinicians in a collection of readable and easy-to-understand reports. In this paper, we will show how CDISC datasets with their required domains and respective variables can be utilized by JMP® Clinical to create clinical trial analysis reports easily and quickly with interactive graphs and tables for use in FDA New Drug Applications and Clinical Reviews. These reports are also ready for inclusion in regulatory submissions such as regulatory documents and clinical study reports to improve reviewability, interpretability, and efficiency of regulatory submission and review.

Structured content and data management—enhancing acceleration in drug development through efficiency in data exchange

Innovation in pharmaceutical therapeutics is critical for the treatment of serious diseases with unmet medical need. To accelerate the approval of these innovative treatments, regulatory agencies throughout the world are increasingly adopting the use of expedited pathways and collaborative regulatory reviews. These pathways are primarily driven by promising clinical results but become challenging for Chemistry, Manufacturing, and Controls (CMC) information in regulatory submissions. Condensed and shifting timelines present constraints that require new approaches to the management of regulatory filings. This article emphasizes technological advances that have the potential to tackle the underlying inefficiencies in the regulatory filing eco-system.Structured content and data management (SCDM) is highlighted as a foundation for technologies that can ease the burden on both sponsors and regulators by streamlining data usage in regulatory submissions. Re-mapping of information technology infrastructure will improve the usability of data by moving away from document-based filings towards electronic data libraries. Although the inefficiencies of the current regulatory filing eco-system are more evident for products that are filed using expedited pathways, it is envisioned that the more widespread adoption of SCDM, across standard filing and review processes, will improve overall efficiency and speed in the compilation and review of regulatory submissions.

A tiered testing strategy based on in vitro phenotypic and transcriptomic data for selecting representative petroleum UVCBs for toxicity evaluation in vivo.

Hazard evaluation of substances of "unknown or variable composition, complex reaction products and biological materials" (UVCBs) remains a major challenge in regulatory science because their chemical composition is difficult to ascertain. Petroleum substances are representative UVCBs and human cell-based data have been previously used to substantiate their groupings for regulatory submissions. We hypothesized that a combination of phenotypic and transcriptomic data could be integrated to make decisions as to selection of group-representative worst-case petroleum UVCBs for subsequent toxicity evaluation in vivo. We used data obtained from 141 substances from 16 manufacturing categories previously tested in 6 human cell types (induced pluripotent stem cell [iPSC]-derived hepatocytes, cardiomyocytes, neurons, and endothelial cells, and MCF7 and A375 cell lines). Benchmark doses for gene-substance combinations were calculated, and both transcriptomic and phenotype-derived points of departure (PODs) were obtained. Correlation analysis and machine learning were used to assess associations between phenotypic and transcriptional PODs and to determine the most informative cell types and assays, thus representing a cost-effective integrated testing strategy. We found that 2 cell types-iPSC-derived-hepatocytes and -cardiomyocytes-contributed the most informative and protective PODs and may be used to inform selection of representative petroleum UVCBs for further toxicity evaluation in vivo. Overall, although the use of new approach methodologies to prioritize UVCBs has not been widely adopted, our study proposes a tiered testing strategy based on iPSC-derived hepatocytes and cardiomyocytes to inform selection of representative worst-case petroleum UVCBs from each manufacturing category for further toxicity evaluation in vivo.

Value and Implementation of the Aggregate Safety Assessment Plan

Aggregate safety assessment involves evaluation of the totality of safety data to characterize the emerging safety profile of a product. The Drug Information Association-American Statistical Association Interdisciplinary Safety Evaluation scientific working group recently published an approach to developing an Aggregate Safety Assessment Plan (ASAP). Creation of an ASAP facilitates a consistent approach to safety data collection and analysis across studies and minimizes important missing data at the time of regulatory submission. A critical aspect of the ASAP is identification of the Safety Topics of Interest (STOI). The STOI, as defined in the ASAP, comprises adverse events (AEs), which have the potential to impact the benefit: risk profile of a product and typically require specialized data collection or analyses. While there are clear benefits to developing an ASAP for a drug development program, multiple concerns may be encountered with implementation. This article uses the examples of two STOIs to demonstrate the benefits and efficiencies gained with implementation of the ASAP in safety planning as well as in optimally characterizing the emerging safety profile of a product.

Real-World Monitoring of COVID-19 Vaccines: An Industry Expert View on the Successes, Challenges, and Future Opportunities

Pharmacovigilance leaders from major vaccine developers describe the learnings from the coronavirus disease 2019 (COVID-19) pandemic in the area of pharmacovigilance and pharmacoepidemiology. The authors aim to raise awareness of the co-operation among vaccine developers, highlight common challenges, advocate for solutions, and propose recommendations for the future in the areas of real-world safety and effectiveness, safety reporting and evaluation, and regulatory submissions. To enable timely evaluation of real-world safety and effectiveness, multi-sponsor study platforms were implemented, resulting in quicker recruitment over wide geographical areas. Future gains could be derived by developing geographically flexible, common protocols and/or joint company-sponsored studies for multiple vaccines and a collective strategy to build low/middle-income country (LMIC) sentinel sites. Safety reporting, signal detection and evaluation was particularly challenging given the unprecedented number of adverse events reported. New methods were required to manage increased report volume while maintaining the ability to quickly identify and respond to new data that could impact the benefit-risk profile of each vaccine. Worldwide health authority submissions, requests for information and differing regulatory requirements imposed significant burden on regulators and industry. Industry consensus on the safety reporting requirements and joint meetings with regulatory authorities markedly reduced this burden for all stakeholders. The most impactful innovations should be undertaken rapidly and expanded to other vaccines and therapeutics, with a multi-stakeholder approach. The authors of this paper make future recommendations and have launched an initiative named BeCOME (Beyond COVID Monitoring Excellence) with a focus on actions in each of the highlighted areas.

Evaluation of chemical grouping workflows for flavor inhalation risk assessment: Selected furan moiety-containing chemicals as a case study

Read-across and chemical grouping approaches are increasingly utilized in risk assessment and regulatory submissions. The European Food Safety Authority (EFSA) has established Chemical Group (CG) 14, which contains furfuryl and furan derivatives both with and without side-chain substituents; however, the rationale for this grouping is not available based on current EFSA documentation. Therefore, this study aimed to identify the chemicals belonging to CG14, evaluate the constituent chemicals for metabolic, biological, and toxicological properties via clustering tools, and apply existing chemical grouping workflows for identifying representative chemicals for this group to support testing strategies. Membership to CG14 was difficult to identify, and varied by EFSA source (e.g., published reports, OpenFoodTox database). Based on predictions from the Organisation for Economic Co-operation and Development (OECD) Quantitative Structure Activity Relationship (QSAR) Toolbox, ChemACE, SMARTCyp, and WhichCyp, as well as data extracted from the U.S. Environmental Protection Agency’s (EPA’s) Toxicity Forecaster (ToxCast) on CompTox Chemicals Dashboard and the European Chemicals Agency (ECHA) Dossier, no suitable metabolic, toxicological, structural, or mechanistic clustering method was identified for CG14. Biological effect data were too sparse to refine the chemical subgroupings within CG14 with confidence based on existing read-across principles for chemical grouping. This paucity of data limits the development of a tiered testing strategy in which more complete testing would be conducted for selected representative CG14 compounds only. Therefore, efforts to generate key pieces of data (e.g., mode of action [MOA], metabolism) for chemical grouping and read-across are needed to apply this workflow to EFSA CG14.

Peer review of a clinical trial protocol: Practical tips for regulatory medical writers, clinicians, and clinical scientists

Protocol development is a critical milestone in the clinical drug development process for all pharmaceutical companies conducting clinical trials. A regulatory medical writer (RMW) plays a crucial role in the protocol development and peer review processes along with different stakeholders. Poor peer review leads to protocol amendments, which delay regulatory submission and increase project costs. Thus, there is a strong need for RMWs and stakeholders to work together during the peer review process to highlight the specific issues that should be addressed before finalisation, which helps in creating effective, efficient, and high-quality protocols. The suggested protocol peer review steps described in this article will help an RMW to plan, coordinate, and deliver this highly important document for global and local clinical trials.

Combining the Target Trial and Estimand Frameworks to Define the Causal Estimand: An Application Using Real-World Data to Contextualize a Single-Arm Trial

Single-arm trials (SATs) may be used to support regulatory submissions in settings where there is a high unmet medical need and highly promising early efficacy data undermine the equipoise needed for randomization. In this context, patient-level real-world data (RWD) may be used to create an external control arm (ECA) to contextualize the SAT results. However, naive comparisons of the SAT with its ECA will yield biased estimates of causal effects if groups are imbalanced with regards to (un)measured prognostic factors. Several methods are available to adjust for measured confounding, but the interpretation of such analyses is challenging unless the causal question of interest is clearly defined, and the estimator is aligned with the estimand. Additional complications arise when patients in the ECA meet the inclusion/exclusion criteria for the SAT at multiple timepoints. In this article, we use a case-study of a pivotal SAT to illustrate how a combination of the target trial and the ICH E9(R1) estimand frameworks can be used to define the target estimand and avoid common methodological pitfalls. We also propose an approach to address the challenge of how to define an appropriate time zero for external controls who meet the SAT inclusion/exclusion criteria at several timepoints.

Meta-Analysis of 49 Roche Oncology Trials Comparing Blinded Independent Central Review (BICR) and Local Evaluation to Assess the Value of BICR.

Blinded independent central review (BICR) of radiographic images is frequently conducted in oncology trials to address the potential bias of local evaluation (LE) of endpoints such as progression-free survival (PFS) and objective response rate (ORR). Given that BICR is a complex and costly process, we evaluated the agreement between LE- and BICR-based treatment effect results and the impact of BICR on regulatory decision-making. Meta-analyses were performed using hazard ratios (HRs) for PFS and odds ratios (ORs) for ORR from all randomized Roche-supported oncology clinical trials during 2006-2020 that had both LE and BICR results (49 studies with a total of over 32 000 patients). Overall, the evaluation bias of LE overestimating the treatment effect compared with BICR based on PFS was numerically small and not clinically meaningful, especially for double-blind studies (HR ratio between BICR and LE: 1.044). A larger bias is more likely to occur in studies with open-label design, smaller sample sizes, or an unequal randomization ratio. The majority (87%) of the PFS comparisons led to the same statistical inference by BICR and LE. For ORR, a high degree of agreement between BICR and LE results was also observed (OR ratio of 1.065), although the agreement was slightly lower than for PFS. BICR did not notably impact the study interpretation nor drive the sponsor's regulatory submission decisions. Hence, if bias can be diminished by appropriate means, LE is deemed as reliable as BICR for certain study settings.

Moving Toward a Question-Centric Approach for Regulatory Decision Making in the Context of Drug Assessment.

The most intuitive question for market access for medicinal products is the benefit/risk (B/R) balance. The B/R assessment can conceptually be divided into subquestions related to establishing efficacy and safety. There are additional layers to the B/R ratio for medical products, including questions related to dose selection, clinical and nonclinical pharmacology, and drug quality. Explicitly stating the actual questions and how they contribute to the overall B/R provides a structure that fosters better informed cross-domain discussions. There is currently no systematic approach in the regulatory setting to assess and establish the acceptability of alternative methods and data sources. In most cases, the medicinal product sponsors tend to prioritize traditional data types and methods, which are well accepted by regulators for inclusion in regulatory submissions. This, in addition to the absence of rigor in the use and validation of new data types and methods, and the limited training of assessors in related fields can lead to increased regulatory skepticism toward new data types and methods. A data-knowledge backbone is needed to mitigate the uncertainty in efficacy and safety characterization. This white paper discusses the value of explicitly redefining and restructuring the regulatory scientific decision making around the scientific question to be addressed. The ecosystem proposed is based on three pillars: (i) a repository connecting questions, data, and methods; (ii) the development and validation of high-quality standards for data and methods; and (iii) credibility assessment. The ecosystem is applied to four use cases for illustration. The need for training and regulatory guidance is also discussed.

Best Practice Recommendations for Electronic Patient-Reported Outcome Dataset Structure and Standardization to Support Drug Development

The electronic patient-reported outcome (ePRO) Dataset Structure and Standardization Project is a multistakeholder initiative formed by Critical Path Institute’s PRO Consortium and Electronic Clinical Outcome Assessment (eCOA) Consortium to address issues related to ePRO dataset structure and standardization and to provide best practice recommendations for clinical trial sponsors and eCOA providers. Given the many benefits of utilizing electronic modes to capture PRO data, clinical trials are increasingly using these methods, yet there are challenges to using data generated by eCOA systems. Clinical Data Interchange Standards Consortium (CDISC) standards are used in clinical trials to ensure consistency in data collection, tabulation, and analysis and to facilitate regulatory submission. Currently, ePRO data are not required to follow a standard model, and the data models used often vary by eCOA provider and sponsor. This lack of consistency creates risks for programming and analysis and difficulties for analytics functions generating the required analysis and submission datasets. There is a disconnect between data standards used for study data submission and those used for data collection via case report forms and ePRO forms, which would be mitigated through the application of CDISC standards for ePRO data capture and transfer. The project was formed to collate and examine the issues arising from the lack of adoption of standardized approaches and this paper details recommendations to address those issues.Recommendations to address issues with ePRO dataset structure and standardization include adopting CDISC standards in the ePRO data platform, timely involvement of key stakeholders, ensuring ePRO controls are implemented, addressing issues of missing data early in development, ensuring quality control and validation of ePRO datasets, and use of read-only datasets.

Conventional Regulatory Submission Drawbacks and Strategies to Avoid Them

Regardless of the size of your company or the stage of your product development, regulatory filings can be difficult. When creating a regulatory submission for approval, there are several steps and room for error. On the other hand, project leaders who are knowledgeable about regulatory submissions can support the effort to foresee, avoid, reduce, and handle these difficulties. In truth, corporations may be able to handle a lot of these issues. The careful navigation of intricate restrictions established by international health authorities is required for the commercialization of novel pharmaceuticals. Extensive internal and external stakeholder interactions are required for the production of pharmaceuticals, as well as cross-functional team coordination in areas including R&D, QA, clinical research, safety, manufacturing, supply chain, marketing, and so forth. At every step of development, companies are in charge of ensuring the security and effectiveness of their medications for human use. To do this, documentation and dossiers must be shared with health authorities regularly. The R&D divisions, CROs, and regulatory agencies of several biopharma, consumer healthcare, and medical device businesses have difficulties in this field. For all businesses to file regulatory filings on time, correctly, and at the appropriate level, there must be clear criteria.

Increasing impact of quantitative methods and modeling in establishment of bioequivalence and characterization of drug delivery.

Increasing impact of quantitative methods and modeling in establishment of bioequivalence and characterization of drug delivery.

Regulatory utility of mechanistic modeling to support alternative bioequivalence approaches: A workshop overview.

On September 30 and October 1, 2021, the US Food and Drug Administration (FDA) and the Center for Research on Complex Generics cosponsored a live virtual workshop titled "Regulatory Utility of Mechanistic Modeling to Support Alternative Bioequivalence Approaches." The overall aims of the workshop included (i) engaging the generic drug industry and other involved stakeholders regarding how mechanistic modeling and simulation can support their product development and regulatory submissions; (ii) sharing the current state of mechanistic modeling for bioequivalence (BE) assessment through case studies; (iii) establishing a consensus on best practices for using mechanistic modeling approaches, such as physiologically based pharmacokinetic modeling and computational fluid dynamics modeling, for BE assessment; and (iv) introducing the concept of a Model Master File to improve model sharing between model developers, industry, and the FDA. More than 1500 people registered for the workshop. Based on a postworkshop survey, the majority of participants reported that their fundamental scientific understanding of mechanistic models was enhanced, there was greater consensus on model validation and verification, and regulatory expectations for mechanistic modeling submitted in abbreviated new drug applications were clarified by the workshop.

Challenges in Implementing Futility Schemes, with Reference to Aducanumab.

Stopping an ongoing clinical trial based on an interim analysis that shows poor outcomes, often referred to as a judgment of "futility", is a familiar feature in current clinical trials practice. Interim data can be misleading, and the implications of prematurely terminating a trial that should not stop are severe. It is thus critical that designs allowing futility stopping be planned and implemented carefully and cautiously. A recent Phase III development program for aducanumab in Alzheimer's disease was halted based on a pre-defined futility guideline, yet based upon updated data and closer examination, the terminated studies became the basis for a regulatory submission. Not surprisingly, this situation generated much controversy and discussion. It provides a good basis for illustrating important principles governing the planning and implementation of futility schemes.

Development of a definition for real-world evidence using the Jandhyala method for observing consensus opinion among medical affairs pharmaceutical physicians

Objective Low rates of inclusion of real-world evidence (RWE) during regulation may arise from lack of clarity and consensus on its definition. A conceptually mature definition of RWE may have pragmatic utility, increasing its inclusion during regulation. The aim was to develop a definition of RWE to promote inclusion in regulatory submissions and assess its conceptual maturity. Methods Thirteen medical affairs pharmaceutical physicians completed two qualitative online surveys to generate items needed in a definition of RWE. Items that reached a consensus index of > 50% (CI > = 0.51) were retained in the final definition. The maturity of the definition was assessed using concept analysis. Results After attrition, 11 participants completed the study and generated 18 items to be included in a definition of RWE. All items reached the consensus threshold and were included. The definition was conceptually mature on three of the four dimensions: the potential for a consensual definition across stakeholders, a description of its characteristics and clear preconditions and outcomes. Further research is needed to delineate the boundaries of RWE. Conclusions A definition of RWE was generated that may increase its inclusion during medicines regulation, especially with further refinement from regulators and other stakeholders.

P227 Patient experiences in ulcerative colitis: conceptual model and review of patient-reported outcome measures

Abstract Background Symptoms of ulcerative colitis (UC) negatively affect patients’ health-related quality of life (HRQoL). The aim of this study was to identify symptoms and impacts experienced by patients with UC, develop a conceptual model (CM) and evaluate available patient-reported outcome (PRO) measures for appropriateness for inclusion in UC clinical studies. Methods We conducted a landscape assessment that included: targeted literature reviews (TLRs) to identify concepts of interest and frequently used PRO measures among patients with UC; label claims searches for US and European regulatory and health technology assessment (HTA) submissions; and US and European clinical trial database searches to identify PRO measures used as primary and secondary endpoints in ongoing clinical trials. Results from the TLR informed a CM of UC. Concepts from the CM were mapped to selected PRO measures. Appropriateness of selected PRO measures for UC populations was evaluated via a gap analysis. Results Fifty-two symptoms and 72 impacts of UC were identified from the TLR. The most frequently reported symptoms were diarrhoea, incontinence/leaking/lack of bowel control, urgency, rectal bleeding, frequent bowel movements and fatigue. The most frequently reported impacts were anxiety, depression, inability to conduct daily activities, embarrassment and affected relationships with others. The CM grouped the 52 symptom concepts into eight dimensions, the 29 impacts proximal to UC into two dimensions and the 43 impacts distal to UC into five dimensions (Figure 1). Of the 69 PRO measures identified, eight were selected for conceptual analysis based on being disease-specific and having evidence of use in regulatory label claims, HTA submissions, as UC clinical trial endpoints and/or having US Food and Drug Administration (FDA) qualification status. The five PRO measures that covered the most concepts when mapped against the CM and included in the gap analysis were: the Inflammatory Bowel Disease Questionnaire (IBDQ); Symptoms and Impacts Questionnaire for UC (SIQ-UC); UC-PRO symptoms modules (UC-PRO-Signs and Symptoms [UC-PRO/SS] and UC-PRO-Systemic Symptoms); UC-PRO impact modules (UC-PRO-Daily Coping [UC-PRO-DC], UC-PRO-Daily Life Impact [UC-PRO-DLI] and UC-PRO-Emotional Impact [UC-PRO-EI]); and Crohn’s and Ulcerative Colitis Questionnaire (CUCQ) (Table 1). All five PRO measures had good or excellent support for content validity; the UC-PRO/SS fully met FDA PRO guidance for content validity and most psychometric properties. Conclusion Based on the CM and PRO measures review, the IBDQ plus UC-PRO/SS are recommended to capture UC symptoms and IBDQ plus UC-PRO impact modules to capture proximal impacts. All PRO measures reviewed require further psychometric evaluation.

Modeling Approaches to Reimagine Stability (MARS) for Enabling Earlier Access to Critical Drugs for Patients with Unmet Medical Needs

FDA's experience to date has shown that completion of stability data requirements is one of the most observed challenges for applicants of New Drug Applications (NDAs) with an expedited review designation. Since NDAs submitted under these expedited pathways often have limited available real-time stability data from the primary batches, Modeling Approaches to Reimagine Stability (MARS) have been proposed to support establishment of tentative retest periods of the drug substance and/or expiration dating period (shelf-life) of the drug product. MARS incorporate statistical principles and available tools as a part of the predictive models. In this study, a data mining exercise has been conducted with regulatory submissions of Investigational New Drug (IND) Applications, NDAs, and Abbreviated New Drug Applications (ANDAs) containing MARS data. The case studies presented herein demonstrate how MARS data has been applied to regulatory scenarios involving prediction of retest and/or shelf-life, bridging major development changes, and confirming that no degradation has been observed or predicted. Using the assumption of a linear time trend for those cases that do not display sufficient degradation to conduct MARS for projection of an expiration date, an analysis of covariance (ANCOVA) model is developed and described herein to test the hypothesis of zero slope by a p-value method. Our results show that the application of MARS adequately supported establishment of a tentative commercially viable retest date/shelf-life, thus enabling earlier access to critical drugs for patients with unmet medical needs.

Association Between Regulatory Submission Characteristics and Recalls of Medical Devices Receiving 510(k) Clearance

Most regulated medical devices enter the US market via the 510(k) regulatory submission pathway, wherein manufacturers demonstrate that applicant devices are "substantially equivalent" to 1 or more "predicate" devices (legally marketed medical devices with similar intended use). Most recalled medical devices are 510(k) devices. To examine the association between characteristics of predicate medical devices and recall probability for 510(k) devices. In this exploratory cross-sectional analysis of medical devices cleared by the US Food and Drug Administration (FDA) between 2003 and 2018 via the 510(k) regulatory submission pathway, linear probability models were used to examine associations between a 510(k) device's recall status and characteristics of its predicate medical devices. Public documents for the 510(k) medical devices were collected using FDA databases. A text extraction algorithm was applied to identify predicate medical devices cited in 510(k) regulatory submissions. Algorithm-derived metadata were combined with 2003-2020 FDA recall data. Citation of predicate medical devices with certain characteristics in 510(k) regulatory submissions, including the total number of predicate medical devices cited by the applicant device, the age of the predicate medical devices, the lack of similarity of the predicate medical devices to the applicant device, and the recall status of the predicate medical devices. Class I or class II recall of a 510(k) medical device between its FDA regulatory clearance date and December 31, 2020. The sample included 35 176 medical devices, of which 4007 (11.4%) were recalled. The applicant devices cited a mean of 2.6 predicate medical devices, with mean ages of 3.6 years and 7.4 years for the newest and oldest, respectively, predicate medical devices. Of the applicant devices, 93.9% cited predicate medical devices with no ongoing recalls, 4.3% cited predicate medical devices with 1 ongoing class I or class II recall, 1.0% cited predicate medical devices with 2 ongoing recalls, and 0.8% cited predicate medical devices with 3 or more ongoing recalls. Applicant devices citing predicate medical devices with 3 or more ongoing recalls were significantly associated with a 9.31-percentage-point increase (95% CI, 2.84-15.77 percentage points) in recall probability compared with devices without ongoing recalls of predicate medical devices, or an 81.2% increase in recall probability relative to the mean recall probability. A 1-SD increase in the total number of predicate medical devices cited by the applicant device was significantly associated with a 1.25-percentage-point increase (95% CI, 0.62-1.87 percentage points) in recall probability, or an 11.0% increase in recall probability relative to the mean recall probability. A 1-SD increase in the newest age of a predicate medical device was significantly associated with a 0.78-percentage-point decrease (95% CI, 1.29-0.30 percentage points) in recall probability, or a 6.8% decrease in recall probability relative to the mean recall probability. This exploratory cross-sectional study of 510(k) medical devices cleared by the FDA between 2003 and 2018 demonstrated significant associations between 510(k) submission characteristics and recalls of medical devices. Further research is needed to understand the implications of these associations.