Andrea Kucek, Katie Klein, Tuaha Liaquat, Aliza Hussain and Justina Wong*
Youreka Canada | yourekacanada.org
This project came in 3rd place in the Youreka Canada National Competition
INTRODUCTION
Pulmonary hypertension (PH) occurs when arterial pressure is 25 mmHg or higher at rest, and is a rare pediatric condition with only 63.7 cases per 1 million children (Rajagopal et al., 2016). There have been numerous clinical trials conducted for adult PH, but due to the small number of pediatric cases, there are a limited number of clinical trials specific to the pediatric population. Hence, the current treatment algorithm is extrapolated from adult data, but this may lead to suboptimal health outcomes for pediatric patients due to the differences in development (Rajagopal et al., 2016). Although clinical trials are considered the gold standard for testing the safety and efficacy of new treatments, the lack of pediatric representation in literature compromises the external validity of clinical trials specific to PH. To ensure that this patient population is accounted for, it is crucial to have an adequate amount of separate pediatric PH clinical trials.
Besides the small number of PH cases in children, there are several other barriers to pediatric research which may account for the low representation in clinical trials. Smith et al. (2010) outlined several of these challenges, such as parental concerns with communication and potential side effects, along with ethical and logistical issues such as consent and assent. Additionally, children tend to be less cooperative due to a lack of comprehension and limits in their attention span, thus more time must be spent on every procedure as compared to the adult population. Children participating in clinical trials tend to have more complications and risks as compared to adult clinical trials. For example, developing children have a lower tolerance to drug toxicity leading to more adverse consequences when greater than acceptable amounts of the drug are consumed.
The aims of this study are twofold: to quantify pediatric underrepresentation in clinical trials for pulmonary hypertension in comparison to adults, and to identify trends in pediatric clinical trials conducted from 2000 to present day.
MATERIALS AND METHODS
The database used for this investigation was the US National Library of Medicine ClinicalTrials.gov. It includes American clinical trials as well as several international studies, both publicly and privately funded. This database also includes all studies required by law to be submitted and registered, described in the FDAAA 80. It was developed by the National Institutes of Health and the Food and Drug Administration, and made available to the public in 2000 (Pasquali et al., 2012).
A keyword search of “pulmonary hypertension” was performed. All resulting interventional studies registered on ClinicalTrials.gov were included if: 1) the start date fell within January 2000 to January 2020, 2) the clinical trial had completed recruitment, and 3) the clinical trial had complete results. We included all studies that fit this eligibility regardless of sex, geographic location, clinical trial phase, and funder types. An interventional study is defined by ClinicalTrials.org to be a study where an investigator assigns an intervention based on a protocol (Pasquali et al., 2012). We excluded studies if none of the participants completed the clinical trial. To evaluate the data from ClinicalTrials.gov, we created a secondary database from the interventional studies included. This included information on the geographical location, dates and duration of the study, participant demographics, primary endpoints, and the results concluded from the trial.
The interventional studies were then analyzed using descriptive analytics to outline the differences between pediatric and adult participant demographics and study characteristics. Categorical variables were reported using relative frequencies, while continuous variables were reported using medians and interquartile range (IQR). The success rate between pediatric and adult clinical trials was compared using a chi-square test. A p-value of <0.05 was defined as statistically significant, and results were presented as mean (M) and standard deviation (SD). Afterwards, the clinical trials containing pediatric participants (any participants under the age of 18) were analyzed separately using descriptive analytics to identify current trends in pediatric PH research. This was done by identifying which interventions resulted in the most successful clinical trials based on the primary endpoint (see Table 2). Interventions were grouped into 14 categories for analysis: single drugs (vasodilators, endothelin receptor antagonists, sildenafil or tadalafil medications), Soluble Guanylate Cyclase (SGC) stimulators, nitric oxide/inhaled nitrite/oxygen, antianginals, bronchodilators, kinase inhibitors, estrogen-related drugs, beta-blockers, and selective serotonin reuptake inhibitors (SSRIs), and combinations of endothelin receptor antagonists and tadalafil/ sildenafil. Other drugs and non-drug procedures with less than two clinical trials were categorized as ‘other’. There were six primary endpoints used for analysis: an increased walking distance in a 6-minute span, improved cardiovascular performance, a decrease in adverse events, improved quality of life, drug dosage related endpoints, and any other endpoints that did not fall into the previously stated categories categorized as ‘other’. We classified the study as a success if the primary endpoint was reached. Clinical trials that met their primary endpoint were coded as “1”, while unsuccessful trials were coded as “0”.
RESULTS
Overall, 111 interventional studies resulted from the keyword search for “pulmonary hypertension” with start dates between January 1, 2000 and January 1, 2020 on ClinicalTrials.gov. Two studies were excluded as they did not have any participants complete the trials, resulting in 109 eligible clinical trials to be analyzed. An analysis of the data was conducted with a total of 11,766 participants enrolled and 9,172 participants completing the clinical trials (see Table 1). The interventional studies we analyzed were in phases 1-4 and took place primarily in Canada, the United States, Europe, and Asia. The age criteria for the studies were either pediatric, adult, or both. There were six trials with a strictly pediatric age criterion. The median participant age was 51.1 years (IQR = 13.25), and a distribution is given in Figure 1. Although the majority of studies looked at PH or pulmonary arterial hypertension (PAH) exclusively, some studies looked at PH in conjunction with other comorbidities such as heart or lung disease. We did not differentiate between the different conditions that were considered in conjunction with PH.
Table 1. Frequency table for describing participant demographics (n = 11766) and study characteristics (n = 109)
Table 2. Frequency table for interventions (n = 14) and primary endpoints (n = 6) used
For the 109 clinical trials analyzed, the median study duration was 32 months (IQR = 30). The median number of participants enrolled in a clinical trial was 34 (IQR = 92), and the median number of participants that completed a clinical trial was 30 (IQR = 89).
We then compared the success rates between the interventional studies including pediatric involvement and studies with only adult participation. In four adult studies and one pediatric study, it was unclear if the endpoint was met so they were excluded from subsequent analysis. Thus, a total of 104 (76 adult and 28 pediatric) interventional studies were analyzed. There was no significant difference in successful trials between the two age groups, X2 (1, N = 104) = 1.264, p = .261, despite there being more adult trials (M = .816, SD = .390) than pediatric trials (M = .714, SD = .460).
We then analyzed the pediatric trials separately. One pediatric clinical trial, which analyzed the frequency of which the specific drug should be taken in a day, was removed as it could not be concluded if the endpoint reached was successful or not. Therefore, 28 pediatric trials were included in this analysis. We found that various interventions including SGC stimulators, antianginal medications, bronchodilators, kinase inhibitors, estrogen-related drugs, and beta-blockers were absent in pediatric clinical trials compared to adult trials.
Generally, the most successful interventions in pediatric PH clinical trials were those that involved vasodilators, sildenafil or tadalafil medications, and endothelin receptor antagonists (see Figure 2). The latter two were involved in some clinical trials that did not reach their primary endpoint, whereas the vasodilator intervention trials always reached their primary endpoint. Overall, these three interventions were the most successful in reaching primary endpoints. These trends in usage of these three interventions from 2009 to 2019 are presented in Figure 3. Additionally, it should also be noted that all clinical trials for SSRIs failed to reach the primary endpoint of the study.
The primary endpoint was most often reached in increased walking distance tests (see Figure 4). Other primary endpoints such as decreased adverse events, improved cardiovascular performance, and endpoints classified as ‘other’ were also relatively successful. The majority of the clinical trials identified the six-minute walk test as their primary endpoint, and although it was primarily reached, it also had the most clinical trials that did not reach this primary endpoint. It should be noted that the primary endpoints classified as ‘other’, improved quality of life, and those that were drug dosage related did not have any clinical trials that did not reach their primary endpoint.
Figure 1. Histograms describing the ages of participants (top left), duration of clinical trials (top right), and number of participants who enrolled in (bottom left) and completed (bottom right) PH clinical trials.
Figure 2. Bar graph comparing the success rates between different interventions used in clinical trials for PH containing pediatric participants. The most prominent interventions are vasodilators, endothelin receptor antagonists, and sildenafil/tadalafil.
Figure 3. Graph showing the usage of the three most prominent interventions for PH in clinical trials containing pediatric participants from 2009 to 2019. It should be noted that these interventions were not used prior to 2009.
Figure 4. Bar graph comparing the success rates between different primary endpoints used in clinical trials for PH containing pediatric participants. The most prominent is increased walking distance.
DISCUSSION
From our database search, there was an evidently smaller number of pediatric clinical trials. There were only six studies with participants solely under the age of eighteen, and 29 studies containing any participants under the age of eighteen. When compared to the 80 studies with only adult participants, there are almost three times as many adult clinical trials compared to trials containing participants under 18. Although there was no statistically significant difference in the number of successful trials between the two age groups, this may be impacted by the much smaller number of pediatric trials available to be analyzed. This underrepresentation of pediatric clinical trials is also noted by many other studies’ which results parallel ours (Sampson et al., 2012). A lack of consensus guidelines from experts has been noted regarding pediatric PH management resulting in limited treatment options compared to what is available for adult patients.
There are several reasons that can account for the large difference in the numbers in all PH trials between pediatric and non-pediatric participants. Most often, consent for a pediatric patient to participate in a clinical trial is obtained from the child’s parent (or legal guardian), and these parents may fear the uncertainty of clinical trials and only want proven treatments for their children. An additional factor contributing to this underrepresentation may be the lack of funding for pediatric trials, as a lower level of allowable risk requires more stringent evidence of safety in pediatric pharmaceuticals compared to adult trials (Kern, 2009). The discrepancy between pediatric disease burden and the number of pediatric clinical trials could possibly be attributed to the fact that pediatric trials rely more on funding from the government and non-profit organizations (Bourgeois et al., 2012). It should also be noted that around one third of pediatric clinical trials done in the United States go unpublished (Harris, 2016). Although our study analyzed the clinical trials mandated by Congress to be registered in ClinicalTrials.org, many of these trials do not make it into literature and thus would have limited clinical benefit for the pediatric population.
From our analyses, it was found that pediatric PH clinical trials with vasodilators, sildenafil or tadalafil medications, and endothelin receptor antagonists were shown to have the highest success rates. This is in accordance with current literature, as Tadalafil medications have been shown to improve exercise tolerance as well as pulmonary hemodynamics (Falk et al., 2010). This drug is well tolerated by patients, and contains positive side effects for diseases such as PH. Vasodilators attempt to reduce pulmonary arterial pressure as well as right ventricular afterload to decrease pulmonary arterial resistance (Barst et al., 1999). This intervention could benefit PH patients because they open up arteries and veins which can attempt to lower pressure in the pulmonary arteries. Sildenafil may also benefit patients with PH, as it decreases the activity of the phosphodiesterase type 5 (PDE5) in the lungs (“Sildenafil (Revatio®), Treatments for Pulmonary Hypertension”, 2013). PDE5 breaks down cyclic guanosine monophosphate (GMP), which relaxes and widens arteries. This discontinuation of eliminating GMPs will lead to lower blood pressure in pulmonary arteries. Finally, endothelin receptor antagonists block endothelin receptors which are vasoconstrictors. Through the usage of these drugs, the arteries will relax and widen, allowing lower pressure in the pulmonary arteries (Correale et al., 2018). Thus, our analysis confirms that these are effective interventions as shown by other studies which demonstrate large scale success for treating PH with these drugs (Langleben, 2007). Conversely, we found that no pediatric PH clinical trials had success when SSRIs were used. Other studies analyzing SSRIs show similar results for this drug in the treatment of PH. It has been concluded that SSRIs lead to a higher mortality rate as well as clinical worsening (Sadoughi, 2013). The association between SSRIs and PH could be due to confounding factors such as depression, which has been found to have a higher prevalence in people with PH. This elevated percentage of depression in patients may counteract the favorable effects of SSRIs. From our analyses, the six-minute walk test was the most commonly chosen endpoint and the one that was most often reached. It is an efficient test for the pediatric patient population, as it evaluates whether the intervention leads to an increase in the walking distance that can be achieved within six minutes. It has been shown to have a strong correlation with peak oxygen uptake obtained by a cardiopulmonary exercise test (Heresi & Dweik, 2011).
There are several limitations to our study. One limitation is that our data and subsequent analysis were solely based on ClinicalTrials.gov. Our study could be improved by including additional databases which would have provided a more comprehensive analysis that would yield more accurate results. Another limitation is that we classified a study as a pediatric clinical trial if they had any participants under the age of 18, even if the study also included adult participants. However, if we had classified pediatric clinical trials as all studies where the participants were strictly under the age of eighteen, we would have had only six purely pediatric studies, which is too few to properly analyze. Additionally, we used primary endpoints to define success and classified it as either ‘yes’ or ‘no’ in regards to whether or not it was successful. Some of the studies had more than one primary endpoint and we did not account for those or any of the secondary endpoints. Furthermore, depending on the nature of the clinical trial it is not always valid to classify success by either ‘yes’ or ‘no’ as we did in this study. In the future, there could be more categorizations to characterize a “successful” trial for a more comprehensive analysis.
CONCLUSION
The aim of this study was to determine the degree to which pediatric patients are underrepresented in clinical trials for PH. We identified 109 clinical trials, of which 29 included participants that were under the age of eighteen. These numbers clearly identify the lack of research for the pediatric population. We also discovered that various interventions including SGC stimulators, antianginal medications, bronchodilators, kinase inhibitors, estrogen-related drugs, and beta-blockers were absent in pediatric clinical trials compared to trials performed with adults. The most successful interventions in pediatric PH clinical trials were those that involved vasodilators, sildenafil or tadalafil medications, and endothelin receptor antagonists. Additionally, increased walking distance tests were the most frequently reached primary endpoint. Other facts to take into consideration regarding the lack of representation of pediatric patients in PH studies is that around one third of pediatric clinical trials in the United States go unpublished, which goes to show that pediatric PH representation may be more prominent if all studies were to be published. The ethical and logistical aspects of using young, developing children in risky trials should also be taken into consideration when analyzing the underrepresentation of pediatric trials.
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ABOUT THE AUTHORS
JUSTINA WONG
Justina is a radiation therapy student currently studying at the University of Alberta. As one of Youreka Canada’s senior investigators in the Edmonton chapter, she enjoys mentoring youth research and strives to foster scientific inquiry and engagement.
KATIE KLEIN
I am a grade 11 Strathcona High School student. I am passionate about academics, maintaining honours with distinction. I enjoy spending time in nature, especially backcountry camping in the Rocky Mountains. Additionally, I love playing basketball and running cross country for my high school teams.
TUAHA LIAQUAT
My name is Tuaha and I am currently a grade 10 student studying at Old Scona Academic in Edmonton. I have a keen interest in the medical sciences, with the future plan of one day becoming a cardiothoracic surgeon. Aside from academics, I enjoy activities ranging from fishing and biking to camping and hiking.
ALIZA HUSSAIN
Hi! My name is Aliza Hussain. I am in the graduating class of 2022 at Old Scona Academic High School. I’ve always been interested in science and research ever since I was young and I love to read, bake, and play the violin!
ANDREA KUCEK
I am a grade twelve student at Queen Elizabeth High School applying for an Honours neuroscience degree at the University of Alberta in the fall. I am an avid reader and book collector, and I enjoy hiking and spending time in nature as well.