Introduction

The U.S. Food and Drug Administration (FDA) serves a critical role in the regulation of medical technologies and pharmaceuticals, ensuring that new drugs and devices meet established standards for safety and efficacy before entering the market. The quality of evidence supporting drug approvals is of paramount importance. It underpins the FDA’s ability to make informed decisions that protect public health, ensuring that new treatments provide therapeutic value without introducing undue risks [1]. Maintaining high standards in the drug approval process is essential to prevent the introduction of therapies that may have adverse effects or insufficient efficacy [2].

The 21st Century Cures Act, enacted in 2016, was part of a broader regulatory and legislative effort to expedite the development and review of medical products. Although the FDA previously permitted approval on the basis of a single pivotal trial when that trial is deemed adequate and well-controlled, the 21st Century Cures Act reinforced and broadened the agency’s flexibility to accept such evidence. In practice, the Act heightened concerns that approvals might increasingly rely on fewer pivotal studies, particularly in contexts where accelerated approval and surrogate endpoints are applied [3–8]. There is ongoing debate about whether these changes might compromise the thoroughness of the evaluation process, particularly in contexts where accelerated approval pathways and surrogate endpoints are utilized [9–12].

The implications of sponsorship and funding in drug approval processes are critical to understanding the potential biases and influences that may affect the integrity of clinical trials. Industry funding, which has become increasingly dominant, raises concerns about the objectivity of research outcomes, as sponsors may have vested interests in favorable results that expedite the approval of drugs. This potential conflict of interest can lead to the prioritization of speed over thoroughness in the evaluation process, particularly under frameworks like those established under the 21st Century Cures Act, which allows for accelerated approvals. Additionally, the diversification of funding sources, including collaborations between industry, government agencies, and academic institutions, introduces complexities in ensuring the transparency and accountability of trial data.

Further, evaluating the reporting of trial results is crucial for ensuring transparency and accountability in the drug approval process [13–15]. The 2017 Food and Drug Administration Amendments Act (FDAAA) introduced penalties for failing to report trial results within one year of study completion. Despite the threat of fines up to $10,000 per day, with a potential ceiling of $1 million, the policy has had limited impact since its implementation in 2017. A key reason for this is the lack of enforcement by the FDA. By 2021, four years after the policy’s introduction, the FDA had issued only four notices of noncompliance and had not collected any fines. Uncollected potential fines were estimated to total $19 billion¹³—a sum greater than five times the FY 2025 congressional appropriation for the agency. This lack of enforcement has resulted in a continued pattern of underreporting, potentially compromising the integrity of the drug approval process [14,15].

Now, eight years following the implementation of the 21^st Century Cures Act, Congress has begun to consider the next generation of the initiative (Cures 2.0) [16]. The proposed Cures 2.0 Act is designed to build on the successes of the original by accelerating medical innovation, expanding access to telehealth, and modernizing the U.S. healthcare system while minimizing its unintended consequences. Key provisions of the bill include enhancing diversity in clinical trials, expanding the use of real-world evidence (RWE) to fulfill post-marketing commitments, and improving the inclusion of patient experience data. Additionally, the legislation seeks to increase Medicare coverage for new health technologies and expand access to telehealth services by removing geographic restrictions.

This study evaluates trends in the number and sponsorship of clinical trials used in FDA novel drug approvals from 2016 to 2024 [17]. Such context may inform discussions about future policy proposals, including whether evolving approval pathways could further affect evidentiary expectations [18].

Methods

We conducted a retrospective review of all Novel Drug Approvals (NDAs) by the U.S. Food and Drug Administration (FDA) from 2016 to 2024. Data on each approved drug were obtained from the FDA’s publicly accessible records, including the number of trials in the FDA report. To gather detailed information on the studies associated with these approvals, we used the National Library of Medicine’s ClinicalTrials.gov database. For each approved medication, we extracted data on the timing and characteristics of each associated study, including the date when each study was first posted, the start date, the primary completion date, and the date when results were reported, if applicable. Additional variables included study design and sponsorship. Sponsorship categories were coded hierarchically: trials were classified as “industry” if industry support was present, even when combined with other sources. Joint industry-government or NIH-other sponsorships were recorded separately to avoid misclassification. All coders collected variables for a subset of approved drugs each year to ensure standardization. We systematically downloaded all standardized fields from ClinicalTrials.gov into a comprehensive dataset for further analysis.

Results

Number of trials in approvals

Between 2016 and 2024, there was a linear decline in the mean number of studies used per approval (Fig 1). In 2016, the mean number of studies was 3.41, which decreased to 3.11 in 2017. This figure continued to decline to 1.50 by 2022. However, in 2023, there was an increase to a mean of 2.49 trials per approval. This was attributable to a single outlier (Brenzavvy; an SGLT2i), which was approved based on nine trials. Without this outlier, the mean number of trials used for approval in 2023 was 1.85. The linear trend toward fewer trials in the approval by year continued in 2024, when the mean number of trials in the approval was 1.39. An Analysis of Variance planned contrast for linear trend was highly significant (F _1/6753 = 417.98,p < .0001).

Download:

• PNG
  larger image
• TIFF
  original image

Fig 1. Mean number of trials in FDA approval by year.

https://doi.org/10.1371/journal.pone.0342878.g001

In addition to the mean number of trials in approvals, we examined the trend in the number of approvals supported by three or more trials. Notably, in 2016, the majority of drugs (59.1%) were approved based on three or more trials. However, by 2021, this proportion had significantly decreased, with only 11.8% of drugs being approved based on three or more trials. Instead, the majority of approvals in 2021 (76.5%) were based on a single trial. By 2024, 69.4% of products were approved on the basis of a single trial, and only 5.6% were approved on the basis of 3 or more trials. The Pearson chi-square test of these findings indicates that the distribution of the number of trials used in drug approvals has changed significantly over the years studied (X² = 48.19; p < 0.001)(Fig 2), with a significant linear decline in the number approved on the basis of 3 or more studies X² = 26.20, df = 8, p < .0001) The Analysis of Variance contrast test for linear trend was highly significant (F _1/6006 = 129.96, p < .001) (Fig 2).

Download:

• PNG
  larger image
• TIFF
  original image

Fig 2. Approvals with one, two, or three or more trials used in FDA approval: 2016-2023.

https://doi.org/10.1371/journal.pone.0342878.g002

Funding sources for studies

Across the observed years, industry funding consistently dominated study sponsorship, with a general upward trend in its share of total funding (Table 1). In 2016, industry-funded trials accounted for 44.6%, while non-industry sources accounted for 55.4%. Over time, the industry’s share steadily increased, reaching 55.2% in 2018 and climbing to 66.4% by 2019 and 80.4% by 2024. During this period, NIH and other government sources played a relatively minor role, contributing less than 3% of total study funding in most years. Regression analysis showed a significant linear trend over years (percent industry funded = 0.037 X year – 73.74; R² = .45, p < .01).

Download:

• PNG
  larger image
• TIFF
  original image

Table 1. Proportion of sponsor types for studies registered in ClinicalTrials.gov by the year of FDA approval for that drug.

https://doi.org/10.1371/journal.pone.0342878.t001

Timing of study results reporting

In addition to examining evidentiary standards, we also assessed the timeliness of results reporting as a secondary outcome, given its importance for transparency. The duration between a study’s primary completion date and the public posting of its results exhibited considerable variability from 2016 to 2023 (Fig 3). Clinical trials demonstrated a similar trend, with the average days to result posting starting at 840.7 days in 2016 and increasing to 1,226 days in 2020. This period was followed by a reduction and subsequent increase. Accordingly, while there were periods of both extension and reduction in the time taken to post results, the average time remained consistently above one year for studies with available results throughout the observed years. The average time to result posting was consistently longer for clinical trials compared to all trials, highlighting differences in reporting timelines between these study types.

Download:

• PNG
  larger image
• TIFF
  original image

Fig 3. Average Days from Primary Completion Date to Result Reporting.

Clinical trials were defined as randomized interventional studies as indicated on ClinicalTrials.Gov.

https://doi.org/10.1371/journal.pone.0342878.g003

Discussion

These findings should be interpreted in the context of longer-term changes in FDA evidentiary standards. Darrow, Avorn, and Kesselheim [10] provided an important history of rigor in FDA drug review. Prior to the 21^st Centrury Cures act, there was a long-term tension between stringent evidentiary standards and pressures for faster access. Early regulation required little more than accurate labeling (1906) and later safety (1938), but true scientific rigor was institutionalized after the 1962 Kefauver-Harris Amendments, which mandated “adequate and well-controlled” trials demonstrating efficacy. This was typically interpreted as at least two randomized controlled studies to guard against bias. Over subsequent decades, however, this standard has progressively softened. Beginning in the 1980s and accelerating through the 1990s–2010s, legislative and regulatory changes (e.g., Orphan Drug Act, Accelerated Approval, Fast-Track, Breakthrough Therapy, and the 21st Century Cures Act) introduced flexibility in both trial design and evidentiary thresholds, allowing approvals based on fewer trials, smaller samples, surrogate endpoints, or even single studies. Empirically, this shift is evident in the decline in approvals supported by two pivotal trials (from about 81% in the mid-1990s to about 53% by 2015–2017) and increased reliance on nonrandomized or uncontrolled evidence. Our findings extend this literature by showing that, between 2016 and 2024, approvals were increasingly supported by fewer studies.

From 2016 to 2024, the number of FDA novel drug approvals increased, while the number of trials supporting each approval declined [11,19]. Requiring at least two studies for approval reflects a core scientific principle: replication. A second study helps confirm that the findings of the first are reliable and not due to chance or bias. Our observation of a decrease in the number of trials used for FDA drug approvals from 2017 to 2024 raises important considerations for the regulatory process and drug development strategies. We observed that more recent approvals were supported by fewer clinical trials [20]. Additionally, our data reveal consistent delays in the reporting of clinical trial results, with average times exceeding one year. These prolonged reporting delays may hinder the timely evaluation of drug safety and efficacy, potentially impacting the regulatory decision-making process and reducing the transparency of the approval pathway. The combination of fewer supporting trials and delayed results reporting raises questions about transparency and the robustness of the publicly visible evidence base.

The study period includes the COVID-19 pandemic, during which FDA processes were disrupted. These disruptions extended beyond delays in results reporting and may have influenced multiple aspects of the approval process, including trial conduct, evidentiary packages, and regulatory decision-making. Notably, the proportion of industry-sponsored studies increased substantially beginning in 2021 (Table 1), and the mean number of trials supporting approvals reached its lowest point that year, at the height of the pandemic. Although the broader trend toward fewer trials per approval predates the pandemic, these factors complicate interpretation of year-to-year changes observed during 2020 and 2021. Additional qualitative analyses comparing review processes before, during, and after the pandemic would be valuable.

Although these temporal trends coincided with broader federal policy and regulatory changes, this observational study cannot determine whether those changes caused the patterns we observed. The post-Cures policy environment has been characterized by greater attention to regulatory flexibility, including circumstances in which approval may be supported by a single pivotal trial. Although more flexible approval pathways may facilitate earlier access to therapies, they may also be associated with approvals supported by less extensive premarket evidence. More rapid dissemination also raised concerns about the long-term safety and effectiveness of drugs that become available to consumers [21].

Of note, the majority of pivotal evidence continued to come from phase 3 trials across all years studied. While the absolute number of phase 3 trials per approval declined in parallel with the overall decrease in trials, we did not observe a compensatory increase in reliance on earlier phase (phase 1 or 2) studies as the primary basis for approval. This suggests that the trend reflects fewer late-stage trials being conducted or submitted per approval, rather than a systematic substitution of early-stage evidence for confirmatory studies

Building on concerns related to the reduced number of trials used in FDA approvals, we examined the funding landscape of clinical trials over the same period. A review of FDA approvals in 2022 showed that 65% of drugs were approved based on a single study, a substantial increase from previous years [22]. Our analysis of funder types for FDA drug approvals from 2016 to 2023 reveals a clear and consistent trend: the increasing dominance of industry funding in studies associated with drug approvals. Industry sponsors accounted for the majority of funding across all years while funding from other sources, including the National Institutes of Health (NIH) and government networks, remained minimal and even declined over time. For instance, the proportion of trials with NIH funding decreased from 2.97% in 2016 to just 0.41% in 2023 (while the NIH’s overall budget has remained level or increased over this time frame). Our observations confirm analogous trends reported by Buchkowsky [23] and others [23,24]. This shift in funding sources has significant implications for the types of evidence presented in support of new drug approvals.

The increasing reliance on industry funding raises concerns about potential conflicts of interest and the influence of sponsors on the design, conduct, and reporting of clinical trials [25]. Research has shown that industry-sponsored trials are more likely to yield favorable outcomes for sponsors’ products, which can influence the approval process and potentially compromise the safety and efficacy of approved drugs [26,27]. The potential for selective reporting and publication bias is heightened when industry sponsors control the narrative around a drug’s efficacy and safety, as they may prioritize the dissemination of favorable results while minimizing or withholding less favorable data.

The implications of this trend for public policy, particularly in light of the proposed Cures 2.0 initiative, are significant. As industry funding becomes more dominant, while journals and ClinicalTrials.gov do mandate sponsor disclosure and author conflicts of interest, there may be a need for greater transparency and accountability in the drug approval process. The FDA may need to revisit its approval criteria to ensure that the increasing reliance on industry-funded trials does not compromise the safety and efficacy of approved drugs [28]. This could involve strengthening requirements for independent replication of industry-sponsored studies or mandating the inclusion of data from trials funded by non-industry sources, such as the NIH, in the approval process. Maintaining public trust in the FDA’s regulatory process is essential, and this can only be achieved by ensuring that drug approvals are based on a comprehensive and unbiased evaluation of all available evidence.

Our analysis also raises concerns about the completion and timing of result reporting in clinical trials, with an evaluation of the timing of result reporting revealing that the average duration between a study’s primary completion date and the public posting of its results consistently exceeded one year throughout the study period (Fig 3). Notably, there were significant fluctuations during the COVID-19 pandemic years of 2020 and 2021. In 2020, the average days to result posting peaked across all study years at 1,068.8 days for all trials and 1,226 days for clinical trials, reflecting substantial delays. These delays may be attributable to the unprecedented pressures and resource reallocations faced by the FDA and research institutions during the pandemic, as well as the expedited approval processes for critical therapies under Emergency Use Authorizations (EUAs). These delays may also reflect broader administrative and operational pressures affecting trial reporting and enforcement. The prioritization of pandemic-related approvals could inadvertently lead to delays in the oversight and timely reporting of results for other ongoing studies. Additionally, while this flexibility is essential for addressing urgent public health needs, it can also mean that certain administrative processes, including result reporting, are deprioritized. Although there was a noticeable reduction in average days to result posting in 2022 – potentially reflecting a return to more typical approval processes – the trend underscores persistent challenges in achieving timely transparency. To this end, more recently, the Food and Drug Omnibus Reform Act (FDORA) of 2022 has further emphasized reforms to accelerated approval, including requirements for confirmatory studies to be underway at the time of approval. These changes may help address some of the concerns identified in our analysis [29].

Our finding of long delays between trial completion and the public posting of results on ClinicalTrials.gov is consistent with other reports in the published literature [30]. Furthermore, the completeness of reporting, particularly regarding adverse events, is often more comprehensive in ClinicalTrials.gov than in corresponding journal articles, underscoring the importance of timely and thorough data dissemination [30]. The variability in trial completion and reporting times also raises concerns about the robustness of the evidence supporting FDA approvals, particularly for drugs approved under accelerated pathways [31]. Delayed or incomplete reporting can hinder independent verification of trial outcomes, which is critical for ensuring that approved drugs meet the necessary safety and efficacy standards. Accordingly, policies could be strengthened by increasing penalties for non-compliance, mandating real-world data collection post-approval, and improving transparency in trial result disclosures. Given the evolving FDA and HHS leadership, federal priorities have the potential to shape how flexibly existing pathways are interpreted and how strongly post-approval commitments are enforced.

Although our study documents approvals based on fewer studies. It does not establish that current practices put patients at greater risk. As part of our broader project, we are tracking downstream outcomes, including boxed warnings and product withdrawals. At present, insufficient follow‑up time and the observational nature of the study design do not allow the determination of whether changes in evidentiary standards are placing patients at greater risk.

Finally, our study did not address increased use of non-RCT methodologies. The 21^st Century Cures Act also loosened the reliance on randomized clinical trials. As an alternative, the act supported greater use of Real-world evidence (RWE), derived from sources such as electronic health records, claims data, and registries. These methods can complement randomized trials but have important limitations [32]. Because treatment is not randomly assigned, RWE studies are vulnerable to confounding, selection bias, and channeling bias, which can produce misleading estimates of treatment effects even with advanced statistical adjustment [33,34]. Data quality is another concern: clinical detail may be incomplete or inconsistently coded, outcomes may be misclassified, and key variables (e.g., disease severity, adherence, patient-reported outcomes) are often missing. Finally, analytic flexibility that allow multiple design and modeling choices raise the risks of reproducibility challenges and selective reporting [35]. For these reasons, most experts view RWE as complementary to, rather than a substitute for, well-conducted randomized controlled trials, particularly when establishing efficacy (Concato & Corrigan-Curay, 2022).

Conclusions

An independent review of all FDA novel drug approvals between 2016 and 2024 identified significant shifts in the FDA drug approval process, particularly in the decreasing number of trials used in approval and the increasing reliance on industry-funded studies. Additionally, the consistent delays in trial result reporting highlight the need for improved mechanisms to ensure the timely dissemination of clinical data. These trends point to the need for policy adjustments, including stronger enforcement of trial reporting requirements, greater transparency, and increased involvement of non-industry funding sources to mitigate potential biases. Moving forward, policies that bolster post-market surveillance, enforce timely and comprehensive trial result reporting, and support independent clinical research are crucial for maintaining the integrity of the drug approval process [37].