Evaluation of factors associated with recruitment rates in early phase clinical trials based on the European Clinical Trials Register data

Abstract

Effective participant recruitment is a critical challenge in clinical trials. Inadequate enrollment of participants can precipitate delays, escalated costs, and compromise scientific integrity. Despite its relevance, particularly during the early phases, it persists as an obstacle in the field of clinical research. The primary aim of this study was to analyze the recruitment rates of early‐phase clinical trials and evaluate their potential associations with key trial characteristics. Using a descriptive and statistical analysis, a research study was conducted based on the early‐phase trials registered at the European Clinical Trials Register (EU‐CTR), spanning the timeframe from January 2017 to December 2021. Among the 194 trials examined, we found median recruitment rates of 68%. A more detailed exploration revealed a greater level of success in terms of recruitment achievement in pediatric trials when compared to trials involving adults, non‐oncologic trials, or those also developed in non‐European countries. It is important to underscore that only 69 trials out of the total managed to conclude recruitment, with the most prevalent reason for premature cessation being the presence of efficacy and safety issues or sponsor's strategy. This number can be greatly improved. Despite certain disparities observed in the information within EU‐CTR, we have successfully determined the recruitment rates of the studies and established associations with some of the clinical trial characteristics analyzed. Owing to the inherent constraints of this study, further research is warranted to gain a comprehensive understanding of the intricate interplay between trial characteristics and their impact on recruitment rates in early‐phase studies.

Study Highlights.

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Despite comprehensive research efforts, encompassing prospective studies involving interviews with both patients and researchers, as well as retrospective literature reviews, including the examination of clinical trial registries, such as clinicaltrials.gov, the exact factors associated with recruitment in clinical trials, especially in early phase clinical trials, remain unknown.

• WHAT QUESTION DID THIS STUDY ADDRESS?

What are the recruitment rates in early‐phase clinical trials and which are the trial factors that can be associated with them in Europe?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This is the first study that has examined the possible factors that can be associated with recruitment rates in early‐phase trials using the European registry European Clinical Trials Register (EU‐CTR). Several noteworthy factors have surfaced that researchers may take into account to improve the recruitment in their respective trials.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Based on our findings, two key areas of improvement come to light. Researchers should carefully consider the significant factors elucidated in this study as they can be useful to enhance recruitment rates by using the information in the design and planification of trials. This, in turn, will help to increase the completion of early‐phase trials, improved trial performance, cost reduction, and, most notably, a direct positive impact on drug development. Additionally, it is worth noting that the EU‐CTR has exhibited certain information gaps, and our study encountered challenges related to data extraction and discrepancies. Regulatory authorities should take heed of such experiences as they work to refine the new European clinical trial registry (Clinical Trial Information System [CTIS]), which became mandatory for interventional drug trial registration as of January 31, 2023. Addressing these issues will contribute to the efficacy and reliability of clinical trial data management within the European regulatory framework.

INTRODUCTION

The process of bringing a new drug to the market is complex and lengthy, taking up to 12–15 years and incurring costs exceeding $1 billion. Following the synthesis, the drug embarks on the preclinical phase. During this phase, in vitro tests and animal studies are conducted to assess the drug's efficacy and safety profile before progressing to human testing. If the molecule demonstrates a favorable safety and efficacy profile, it proceeds to the clinical research stage, ¹ , ² characterized by a sequence of trials spanning from phase I to phase III, until reaching a marketing authorization by the regulatory authorities. ³ Out of the whole set of compounds tested at the preclinical stage, no more than five are tested on humans and, in the most favorable scenario, only one obtains the approval for therapeutic use. ⁴

In accordance with the literature, only a minority of clinical trials recruit the planned number of patients, ⁵ , ⁶ thereby implicating potential shortcomings in designed recruitment strategies or study designs and representing a constant challenge in the course of clinical trials. ⁷ The underlying reasons distinguishing trials that achieve their intended enrollment from those that do not, remains unknown. Although measures for enhancing recruitment have been proposed, it is yet unknown whether these strategies are being adopted. ⁸

The failure to reach the intended number of participants has implications spanning from the statistical power, the trial's internal and external validity, and the financial cost. Protracted timelines in research completion necessitate increased resource allocation, thereby increasing the financial outlay required for trial execution. ⁹ Furthermore, the repercussions extend to the patients, as the diminished success of clinical research translates into delays in accessing new treatments.

Recruitment assumes paramount significance in the context of early‐phase trials, because they constitute the first step in clinical research and their results establish the foundation for subsequent investigations. This stage of clinical development is characterized by lack of information concerning the body's response to the investigational compound. The primary objective of these trials encompasses safety, determination of the possible therapeutic dose, and acquisition of preliminary pharmacokinetic and pharmacodynamic insights. ¹⁰

Owing to the distinctive attributes inherent to phase I trials, the task of recruitment could represent a challenge. These trials, upon their design and objectives, may recruit healthy subjects or patients. The majority of phase I trials are conducted with the involvement of healthy volunteers, whereas patients are typically enrolled in oncology phase I studies or in studies involving advanced disease stages or serious diseases. ¹¹

In the context of patients' participation, several factors have been reported that may influence their non‐participation in the study. These factors encompass considerations, such as patient's functional status, decompensated biochemical or hematological parameters, and rapid progression of the disease. Moreover, aside from medical factors, the main non‐medical rationale underlying lack of patient recruitment is related to uncertainty of benefit–risk balance and concerns about toxicity. ¹²

In numerous instances, it has been documented that a pivotal factor influencing recruitment is the lack of patient engagement in the trial's design. Furthermore, the absence of accessible information regarding the study outcomes can lead patients to feel uninformed and undervalued, thus exerting a negative influence on their willingness to participate in clinical research. ¹³

This is noteworthy, as trial design has been recognized as a principal factor that significantly impacts on the subjects’ participation. Elements such as being randomized into an arm receiving placebo are frequently regarded as a barrier to enrolling into a clinical trial. Additionally, demographic factors have also been identified as playing a substantial role in influencing trial participation. ¹⁴

In the context of healthy volunteers, for whom the investigational product is not anticipated to yield any clinical advantage, except in the instance of vaccines, altruism and financial gain have been frequently reported as primary motivating factors for participation in clinical trials. Certain studies have observed that economic incentives can lead to a higher participation rate among individuals from lower socioeconomic strata. ¹⁵

As previously described, the enrollment of research participants can be subject to the influence of various factors. Many of these factors have been discerned through surveys, studies, and interviews involving participants, and, in case of minors, their parents, as well as investigators. ¹⁶ , ¹⁷ Nevertheless, certain limitations exist in some of these studies, including inadequately sample size justification, reliability, and validity of research instruments, and challenges in the collection of data. ¹⁸ Furthermore, none of the aforementioned research endeavors has offered comprehensive list of facilitators and barriers to recruitment that effectively address this issue. It is important to underscore that sample size calculation is a crucial aspect to minimize risks while ensuring sufficient statistical power, particularly in pediatric trials. ¹⁹

Historically, children were excluded from research, primarily owing to concerns related to their vulnerability. However, a turning point occurred with the publication of guidelines by the National Institute of Health in the United States in 1998, which emphasized the inclusion of children unless there were scientific and ethical reasons to prevent it. ²⁰ In the context of pediatric trials, the process of obtaining informed consent necessitates the consent of parents or legal guardians, in conjunction with the child's assent when dealing with mature minors. ¹⁹

According to the aforementioned factors, there is a clear necessity to enhance our comprehension of recruitment rates, particularly in early‐phase trials. Through the enhancement of our understanding of study designs and characteristics that may impact trial recruitment, we can uncover opportunities to enhance recruitment efforts.

For this study, we have queried the European clinical trial registry (EU‐CTR), a public database where main data pertaining to interventional clinical trials with drugs conducted in Europe are registered. Our aim was to analyze the recruitment rates of early‐phase clinical trials spanning the period from 2017 to 2021 to assess their association with the trial's main characteristics.

METHODS

Data extraction from the European Registry of Clinical Trials

The EU‐CTR registry constitutes the database in Europe where all interventional clinical trials with drugs that are being developed in Europe should be registered.

The EU‐CTR was queried in January 2022, with two distinct searches conducted. In both the timeframe spanned from 2017 to 2021.

The first search focused on identifying pediatric early‐phase studies (phase I and phase I–II/III), that included population categorized by the following terms “adolescent,” “children,” “preterm newborn,” infants,” “in utero,” “new born,” “under 18,” and “infant and toddler.” Subsequently, all identified studies were subjected to additional filtering to take into account those completed and with their results published in the EU‐CTR.

The second search targeted adult early phase studies and used the term “adult.” Similar to the previous search, filtering criteria were applied to isolate studies that had reached completion and had published their results in the EU‐CTR.

For each study, we extracted from the EU‐CTR information on projected and real recruitment, sponsor classification, therapeutic area, type of population, study phase, participating countries, and whether the study was controlled or not. Subsequently, we established an Excel database that compiled all studies and their respective data for the subsequent analysis.

No ethical review or informed consent was required as this was a review of a publicly available database in which the aggregated information remained dissociated from any individual identities or confidential particulars.

Descriptive: Study variables

• Premature termination: To determine premature terminations, we leveraged the information within EU‐CTR's results section, using the query “Was the trial ended prematurely?” Due to disparities in updates provided by individual countries regarding the study protocol's progress at a national level, we relied exclusively on the data documented in the Results section, as it represented the global outcomes of the trial. Reasons behind these premature terminations were identified from the EU‐CTR results section and categorized into six groups: sponsor‐driven strategic decisions, slow or insufficient recruitment, logistical and development hurdles (coronavirus disease [COVID] reasons, not enough personnel and lack of research partnerships), regulatory authority recommendations, lack of efficacy or safety problems, and “not available” for those instances were no reasons were reported.

• Type of patient: The information regarding whether the trials enrolled patients, healthy volunteers, or both was directly extracted from the protocol section within the EU‐CTR.

• Design: A trial was classified as controlled if the protocol section indicated the presence of placebo or comparator.

• Trial phase: The trial phase was extracted from the EU‐CTR protocol section. In cases where studies reported phase I and phase II, they were considered as phase I–II studies. The same applied to phase I–III trials.

• Type of sponsor: The term “Academic sponsor” was defined as non‐commercial, as indicated in the EU‐CTR, whereas “Industry sponsor” was assigned to sponsors with commercial profit.

• Country: The countries where each trial was conducted were determined from the protocol and results sections at theEU‐CTR. Given that all studies in the EU‐CTR are conducted in Europe, we categorized the studies into two groups: those also conducted outside the European Union and those conducted in United Kingdom (which was originally part of the European Union but ceased to be in 2020).

• Therapeutic area: The therapeutic area is a mandatory field in the EU‐CTR protocol section and we classified them into 15 categories: cancer, cardiovascular diseases, skin and connective tissue diseases, blood and lymphatic system diseases, respiratory tract diseases, digestive system diseases, immune system diseases, nervous system diseases, genetic diseases, congenital and familial diseases, hormonal diseases, mental diseases, musculoskeletal diseases, nutritional and metabolic diseases, eye diseases, and infections. To facilitate the analysis of recruitment rates, we further grouped the therapeutic area into two groups: oncology trials and trials in other therapeutic areas. This categorization was essential due to the significantly high number of trials specifically related to oncology.

• Drug type: The information regarding the drug type was extracted from section D of the EU‐CTR protocol field and classified into four categories: biological origin, chemical origin, advanced therapy, and not detailed.

• Recruitment rates: Recruitment rates were calculated for each study by considering the total number of subjects recruited globally, detailed in the Results section of the EU‐CTR and the planned recruitment detailed in the protocol section. Regarding the planned recruitment, the EU‐CTR provides separate protocols for each participating country in a study, resulting in considerable variability in the global planned recruitment data across these protocols for a single study. To ensure consistency, we selected the smallest planned recruitment number indicated, considering protocols associated with each study.

• Recruitment achievement: Trials with achieved recruitment were those that met or exceeded (recruitment 100% or more) the planned recruitment, whereas trials categorized as having incomplete recruitment were those that did not achieve the planned recruitment rates (recruitment <100%).

• Study duration: The intended study duration was retrieved from the protocol section and the real duration was calculated based on the real start date and the global end date of the trial from the EU‐CTR. Time extension was noted when the trial duration exceeded the initially planned timeframe.

Statistical analysis

A descriptive analysis of the variables was performed, showing the medians and interquartile ranges (IQRs) in the case of quantitative variables, and absolute and relative values in the case of qualitative variables. To assess the association between the recruitment rates and the different trial characteristics, a descriptive‐univariate analysis of all variables was carried out. These rates were presented in median and IQR. For comparisons of independent samples, the Mann‐Whitney U test and the Kruskal‐Wallis test were used. The calculations were carried out with the statistical program R (version 4.0.1).

RESULTS

Between January 1, 2017, and December 31, 2021, a total of 11,077 trials were registered within the EU‐CTR database. Among these, 1033 were early‐phase studies, with 881 targeting the adult population and 322 focusing on pediatric population. Trials lacking complete data or results within the EU‐CTR database and those not designated as either completed or prematurely terminated were excluded from the data analysis, as they did not provide conclusive recruitment data. Consequently, our study included a total of 194 early phase clinical trials: One hundred twenty‐five studies (64.43%) solely involving adult population, 44 (22.68%) exclusively concentrating on the pediatric population, and 25 (12.88%) encompassing both adults and pediatrics (Figure 1).

FIGURE 1.

Disposition plot of the trials extracted from European Clinical Trials Register (EU‐CTR) within the period: January 2017 to December 2021.

Among these trials, a remarkably high proportion, specifically 88 (45.36%), reported premature terminations. It is worth noting that the leading cause was the absence of efficacy or safety concerns (31.82%). This was closely followed by the sponsor's decision for strategic reasons (29.55%) and the slow or insufficient recruitment (11.36%; Table 1). Interestingly, a subset of 16 studies (18.18%) declared premature terminations without providing details regarding the underlying reasons.

TABLE 1.

Number of studies that were prematurely ended according to the causes.

Reasons for early termination	N = 88
Sponsor's strategy	26 (29.55%)
Slow or insufficient recruitment	10 (11.36%)
Logistical and development problems	6 (6.82%)
Authorities’ recommendation	2 (2.27%)
Lack of efficacy or safety reasons	28 (31.82%)
Not detailed	16 (18.18%)

The primary characteristics of the studies were described according to the type of participants (adult population, pediatric population, and encompassing both groups). A summary of these characteristics is provided in Table 2. It is noteworthy that the predominant proportion of trials constituting 91.71% involved patients rather than healthy volunteers. Furthermore, the majority of these trials were conducted without control groups.

TABLE 2.

Descriptive table regarding the trial characteristics according the population included.

	N	Adults	Pediatrics	Adults and pediatrics
Type of patient
Healthy volunteer	11	7 (63.63%)	3 (27.27%)	1 (19.09%)
Patient	177	112 (63.28%)	41 (23.16%)	24 (13.56%)
Healthy volunteer and patient	5	5 (100%)	0	0
Design
Not controlled	105	60 (57.14%)	29 (27.62%)	16 (15.24%)
Placebo/comparator	79	60 (75.95%)	13 (16.46%)	6 (7.6%)
Trial phase
I	49	7 (14.29%)	33 (67.35%)	9 (18.37%)
I/II	134	109 (81.34%)	9 (6.72%)	16 (11.94%)
I/III	9	8 (88.89%)	1 (11.11%)	0 (0%)
Sponsor
Academic	21	14 (66.66%)	4 (19.05%)	3 (14.29%)
Industry	172	111 (64.53%)	40 (23.26%)	22 (12.80%)
Non‐EU countries
UK	91	53 (58.24%)	25 (27.47%)	13 (14.29%)
Outside EU	141	84 (59.57%)	38 (26.95%)	19 (13.48%)
Therapeutic area
Cancer	100	77 (77%)	13 (13%)	10 (10%)
Cardiovascular diseases	7	5 (71.43%)	2 (28.57%)	0 (0%)
Skin and connective tissue diseases	6	3 (50%)	1 (16.67%)	2 (33.33%)
Blood and lymphatic system diseases	6	2 (33.33%)	3 (50%)	1 (16.67%)
Respiratory tract diseases	9	5 (55.56%)	4 (44.44%)	0 (0%)
Digestive system diseases	1	1 (100%)	0 (0%)	0 (0%)
Immune system diseases	6	4 (66.67%)	2 (33.33%)	0 (0%)
Nervous system diseases	4	4 (100%)	0 (0%)	0 (0%)
Genetic, congenital, and familial diseases	11	5 (45.45%)	2 (18.18%)	4 (36.36%)
Hormonal diseases	2	0 (0%)	2 (100%)	0 (0%)
Mental diseases	2	0 (0%)	1 (50%)	1 (50%)
Musculoskeletal diseases	4	2 (50%)	0 (0%)	2 (50%)
Nutritional and metabolic diseases	4	0 (0%)	4 (100%)	0 (0%)
Eye diseases	4	2 (50%)	0 (0%)	2 (50%)
Infections	22	10 (45.45%)	10 (45.45%)	2 (9.10%)
Drug type
Biological origin	67	50 (74.63%)	10 (14.93%)	7 (10.45%)
Chemical origin	100	56 (56%)	32 (32%)	12 (12%)
Advanced therapy	17	11 (64.71%)	2 (11.76%)	4 (23.53%)
Not detailed	10	8 (80%)	0 (0%)	2 (20%)

Abbreviations: EU, European Union; UK, United Kingdom.

Regardless of the population under consideration, trials sponsored by the industry were predominant, with noteworthy 89.12% of studies receiving funding by non‐academic sponsors.

Regarding the geographic location of these trials, participation of countries outside of European Union was evident in more than half of the studies encompassing a total of 141 studies.

Cancer research, followed closely by research on infectious diseases, emerged as the primary therapeutic areas of focus for the majority of trials. Nevertheless, it is worth highlighting that the number of cancer trials significantly outnumbered studies in infectious disease studies, with 78 more trials dedicated to cancer research.

In terms of the type of compounds under evaluation, drugs of both chemical and biological origin were the most frequently evaluated, especially in phase I/II studies (Table S1).

In the context of the overall recruitment outcomes, within the study cohort of 194 analyzed trials, four studies either did not provide information about their recruitment status or remained inconclusive due to discrepancies within the registry. Out of the remaining studies, 121 (63.68%) failed to attain their predetermined recruitment targets and within this subgroup, a total of 88 studies underwent premature end.

Conversely, a contrasting subset of trials, totaling 69 in number (36.32%), successfully achieved their intended recruitment objectives. Upon comparison of the recruitment achievements across different trial types, a statically significant discrepancy became apparent. Specifically, the attainment of recruitment goals exhibited a notable disparity between pediatric and adult trials, with a p value <0.002 (Table 3).

TABLE 3.

Number of studies according to the type of subjects included that achieved or not the planned recruitment.

Has recruitment been achieved?	Overall (N = 190)	Yes (N)	No (N)	p value
Adults a	121	36 (29.75%)	85 (70.25%)	0.002
Adults and pediatrics	25	7 (28%)	18 (72%)
Pediatrics	44	26 (59.10%)	18 (40.90%)

^a Four clinical trials not reported the data.

To assess compliance with the stipulated recruitment timeframe, as outlined in the EU‐CTR, we studied the aforementioned mentioned trials. Our findings revealed that studies that granted time extensions exhibited a greater propensity to achieve their predefined recruitment targets. Specifically, among the 69 trials in which recruitment goals were met, 54 (equivalent to 83.1%) availed themselves of time extensions, a disparity that was found statically significant (p < 0.002).

In an effort to elucidate the potential factors impacting trial recruitment, recruitment rates for each of the variables under consideration were computed. Table 4 provides a comprehensive overview of the analysis pertaining to factors that may influence the trial recruitment rates. Statistically significant differences were discerned in several variables, such as the type of population, where pediatric studies exhibited a notably higher recruitment rate, with a median recruitment rate of 100%.

TABLE 4.

Recruitment median rates for each trial variable.

Variables	N	Recruitment rate median (IQR)	p value
Global		68.00 (20.00–103.02)
Sponsor	193		0.615
Academic	21	68.00 (18.30–88.90)
Industry	172	68.10 (20.00–103.10)
Type of population	194		0.005
Adults	125	53.40 (17.00–100.50)
Pediatrics	44	100.00 (44.55–112.17)
Adults and pediatrics	25	80.20 (39.10–100.00)
Trial phase	191		0.007
I	49	95.80 (53.30–106.80)
I/II	133	51.40 (17.00–100.00)
I/III	9	103.70 (9.5–104.3)
Controlled	184		0.099
Not controlled	105	55.00 (18.40–100.95)
Placebo/comparator	79	91.60 (31.60–104.15)
Type of patient	193		0.140
Healthy volunteer	11	100.00 (90.40–103.05)
Patient	177	65.80 (18.33–103.02)
Healthy volunteer and patient	5	33.30 (33.30–98.10)
Therapeutic area	194
Oncology	100	49.05 (16.08–100.88)
Other	94	91.70 (33.30–104.42)	0.019
Type of drug	67		0.332
Biological origin	10	80.60 (36.40–102.60)
Chemical origin	0	68.00 (17.45–104.95)
Advanced therapy	17	31.60 (20.00–83.80)
UK participation	194
No	103	67.95 (18.33–100.38)	0.293
Yes	91	68.00 (24.50–105.12)
Non‐EU country participation	194
No	53	27.30 (5.20–93.65)	<0.001
Yes	141	80.60 (33.30–105.00)

Abbreviations: EU, European Union; UK, United Kingdom.

Phase I and phase I–III trials demonstrated notably higher median recruitment rates when compared to phase I–II trials. Furthermore, the therapeutic area also emerged as a significant determinant, with higher recruitment rates were observed for trials in therapeutic areas other than oncology. Geographic locations were found to exert a discernible influence on recruitment rates, with trials conducted in countries beyond the European Union exhibiting elevated median recruitment rates (p value <0.001).

DISCUSSION

Despite the importance of early‐phase trials, a significant portion of these trials face premature termination and fail to achieve their recruitment objectives. In order to shed further illumination upon the matter of recruitment rates in early‐phase trials and endeavor to establish potential associations with clinical trial factors within the context of the European landscape, the present study has been undertaken.

Our research represents the first endeavor using the EU‐CTR to systematically extract early‐phase recruitment rates and examine their association with trial characteristics. It is noteworthy that prior analogous investigations predominantly relied on data sourced from the American registry, clinicaltrials.gov. Furthermore, the majority of studies focused on later phases of clinical trials, with limited attention devoted to early‐phase or have mainly consisted of studies documenting their individual recruitment experiences, or qualitative research involving the administration of questionnaires or interviews to both patients and physicians, aimed at assessing factors impacting trial recruitment. ²¹ , ²²

Our results show how almost half of the studies (45.36%) have premature endings. This constitutes a significantly high number worth considering. A comprehensive examination of clinical trial terminations within the Spanish context revealed a lower incidence of premature termination, 21.3% in phase I trials. The rationale underlying these terminations was multifaceted, with patient recruitment challenges accounting for 25%. ²³ Other studies, also showed that the most frequently cited reasons in literature for such terminations pertain to substantial risk–benefit imbalances for patients, scientific challenges associated with the intervention, logistical impediments such as staffing shortages or inadequate financial resources, and delayed or inadequate recruitment efforts. ²⁴ Similarly, our study findings reveal same causes but, interestingly, the prevalent cause of early termination was attributed to the lack of drug efficacy followed by the sponsor's decision for strategic reasons and inadequate or insufficient recruitment, whereas for the Spanish study it constituted the first cause. All of these data hold significant importance as they demonstrate that a substantial number of studies that terminate prematurely do so due to reasons that may suggest inadequate planning or study design. This is a crucial consideration for future research endeavors.

Regarding recruitment rates, our findings revealed that the trials included in our study exhibited a median recruitment rate of 68%, indicating that just over half of the studies achieved their planned recruitment. Among the total trials encompassed within this investigation, only 36.32% successfully attained the predetermined number of recruited participants. These results closely align with prior research, which has consistently indicated that recruitment in randomized controlled trials (RCTs) typically falls within the range of 31% to 60% of the originally intended enrollment. ²⁵ For instance, a separate study conducted in the United Kingdom between 2014 and 2016 reported that only 40% of RCTs achieved full recruitment. ²⁶ In light of these comparisons, our data underscore the fact that early‐phase trials demonstrate slightly higher recruitment rates to those observed in other trial categories, but the number of trials that achieves recruitment has remained relatively stable over the past 5 years.

Our analysis has revealed a noteworthy trend: trials exclusively focused on pediatric populations exhibit significantly higher median recruitment rates, standing at 100.0%, in comparison to studies involving only adult participants (53.40%) or those encompassing both age groups (80.20%). This observation contradicts prevailing literature, which often posits that recruiting children is inherently more challenging than adults due to the relatively low prevalence of certain pediatric conditions and the necessity of obtaining informed consent from both parents while respecting the autonomy of the child. ²⁷ Indeed, other studies have indicated that a quarter of adult‐focused trials experience premature termination due to inadequate patient recruitment, whereas this figure rises to 40% in the case of pediatric trials. ²⁸ Nonetheless, it is essential to acknowledge that there exist studies supporting our findings. A recent investigation in Spain dedicated to pediatric cancer research documented notable improvements in recruitment rates over recent years. These positive trends are attributed, in part, to the 2006 European Pediatric Regulation, which mandates the development of pediatric investigation plans prior to authorizing medicines intended for adult use. ²⁹

In the context of oncology trials, our findings have unveiled substantially lower median recruitment rates, standing at 49.05%, in stark contrast to the notably higher rates observed in other therapeutic domains, which average around 91.70%. This discrepancy in recruitment rates in oncology trials has been a recurring concern among researchers. One explanation lies in the common practice of excluding patients based on stringent criteria, such as chronic viral infections, prior malignancies, or the presence of metastatic disease. ³⁰ Furthermore, a study conducted by Wong et al. ³¹ corroborated this observation by highlighting that oncology trials tend to exhibit reduced levels of competition in comparison to trials conducted in other therapeutic realms.

In the realm of pediatric oncology, where a substantial portion of investigations have previously undergone testing in adults, it is recommended to undertake trials that comprehensively evaluate both safety and efficacy, often characterized as phase I/II. ³² Within our study, a significant proportion of trials adopted this phase I/II. However, it is noteworthy that higher recruitment rates were associated with trials categorized as either phase I or phase I–III. This observation may be attributed to the fact that the phase I/II category included a larger percentage of oncology‐focused studies constituting 60.15% of the total, as opposed to 39.85% in other therapeutic domains.

It is imperative to underscore that among trials that successfully met their pre‐established recruitment targets, a substantial majority (83.1%) necessitated extensions beyond their originally planned durations, thus prolonging their overall timelines. This pattern aligns with findings from previous research, which indicated that approximately one third of RCTs extended their recruitment period in an endeavor to bolster participant enrollment. ²⁶ Likewise, a parallel research, akin to our own, which studied recruitment metrics in clinicaltrials.gov, unveiled that nearly 80% of the trials fell short of their recruitment timelines. It is crucial to recognize that each day of delay in recruitment can incur substantial financial losses for sponsors. ³³ Furthermore, it is well‐established that research delays can lead to delays in efficacious knowledge and treatments to be adopted as standard of care protocols. ³⁴

According to literature, during the last years, efforts to enhance recruitment in clinical trials have included the strategic expansion of trial locations, with a particular focus on regions where a higher prevalence of certain diseases exists. Industry sponsored trials have engaged with countries in Eastern Europe, Latin America, and Asian countries as China and India. This approach has been motivated by the recognition that these countries offer advantages in terms of cost‐efficiency, as they are capable of enrolling a larger number of patients within shorter timeframes. ³⁵ , ³⁶ Our data underscore significantly better recruitment rates when non‐European countries participated in the trials.

The nature of the sponsor constitutes another dimension that has been studied. It has been stated that trials sponsored by industry usually demonstrate superior recruitment rates compared to those sponsored by investigators. ³⁵ This disparity has been attributed due to the limited professionals at place dedicated to research and poor funding within academic trials. However, our study yielded findings in this regard. Despite the predominant presence of industry sponsor in the majority of trials analyzed, the median recruitment rates were similar between academic or industry sponsor (68.0% vs. 68.10%). This shows how the academia has improved recruitment rates in its early phase studies.

This study bears certain limitations. It is designed as a qualitative analysis, focusing on trial characteristics that could affect the recruitment rates in early‐phase clinical trials. Our data was acquired at a single timepoint from the EU‐CTR, which, while generally regarded as a relatively comprehensive and updated registry, does not encompass, in some cases, complete clinical trials information and presents variability among different countries, introducing a degree of heterogenicity into the recorded data. Furthermore, it is crucial to acknowledge the presence of regulatory disparities governing trial registration and results dissemination, which can vary depending on the type of clinical trial. For instance, in accordance with the 2012 directive (2012 EC 2012/c302/03), ³⁷ sponsors must ensure the disclosure of trial results to the EMA within 12 months of completion for trials registered with EU‐CTR since 2004. However, phase I trials are exempt unless they are designated as part of a pediatric investigational plan. We postulate that this regulatory aspect may contribute to instances where clinical trials results or the rationales behind premature terminations are not consistently reported. We have furthermore observed that data quality issues may arise due to the trial information is submitted in different countries by different people.

Nonetheless, we can conclude that our study has identified a median recruitment rate of 68% for early‐phase trials. Only 36.31% of the trials achieved their planned recruitment goals, which is lower than what is reported by other authors previously. This highlights the persisting challenges associated with recruitment. Additionally, 45.36% of the trials were prematurely ended, with reasons primarily related to the efficacy, safety, or sponsor's strategy instead of recruitment reasons as stated in other studies. But, nonetheless, these factors may suggest potential issues with trial design that could affect the recruitment rates, emphasizing the importance of addressing these aspects in future research endeavors.

Pediatric trials have demonstrated exceptionally favorable recruitment rates, in contrast to what has been reported by other studies. Similar to the literature, our study shows the recruitment challenges faced by oncologic trials when compared to other therapeutic areas, and the improved recruitment seen with the participation of non‐European countries.

The identified factors, can help when designing early‐phase trials or when planning the efforts to be made for recruitment as more attention should be paid to the factors that can be associated to low recruitment.

This study represents the first investigation into potential trial factors associated with recruitment rates by utilizing the European registry EU‐CTR as a comprehensive data source. Notably, several significant factors have emerged, offering valuable insights that researchers can consider when seeking to enhance recruitment strategies in their respective trials.

AUTHOR CONTRIBUTIONS

P.M.A., P.P., A.J.C., and A.M.B. wrote the manuscript. P.M.A., A.J.C., and A.M.B. designed the research. P.M.A., M.U., A.J.C., and A.M.B. performed the research. P.M.A., M.J., A.J.C., and A.M.B. analyzed the data.

FUNDING INFORMATION

No funding has been received for this research.

CONFLICT OF INTEREST STATEMENT

The authors declared no competing interests for this work.

Supporting information

Table S1

Moraga Alapont P, Prieto P, Urroz M, Jiménez M, Carcas AJ, Borobia AM. Evaluation of factors associated with recruitment rates in early phase clinical trials based on the European Clinical Trials Register data. Clin Transl Sci. 2023;16:2654‐2664. doi: 10.1111/cts.13659