Regulatory initiatives: brief historical overview

Although a comprehensive overview of paediatric drug/device development regulation is beyond the scope of this manuscript, a brief review of recent legislative initiatives will be helpful to better understand the current clinical trials landscape. Figure 1 summarises initiatives from the past 2 decades designed to encourage paediatric trials in the United States of America and Europe. Landmark initiatives include the 1998 “Pediatric Exclusivity” provision, the 2002 Best Pharmaceuticals for Children’s Act, the 2003 Pediatric Research Equity Act, and the 2007 Paediatric Regulation. Collectively, they have established regulatory mandates, incentives, and oversight mechanisms designed to advance the paediatric evidence base. These efforts have been tremendously successful. In the United States of America, >480 paediatric trials enrolling >175,000 study patients have been conducted over the past decade with similar recent successes documented in Europe. ^{12 – 14} From a financial standpoint, these trials have injected an enormous amount of capital into paediatric research. Li et al estimated costs for a subset of trials conducted under the auspices of the Pediatric Exclusivity provision between 2002 and 2004.Reference Li, Eisenstein and Grabowski ¹⁵ The median cost to the sponsor to conduct the required paediatric drug studies was $12.34 million (with a range from $5.13 to 43.80 million). Despite this upfront expense, the economic return from patent extension – the principal financial incentive for study sponsors – is typically well worth the investment with an estimated median net economic benefit of $134 million (with a range from −$8.9 to +$507 million) for the nine products studied.Reference Li, Eisenstein and Grabowski ¹⁵ Not surprisingly, after decades of inaction, the pharmaceutical industry has now enthusiastically embraced paediatric drug study with an almost sixfold increase in the average annual number of trials conducted in children to evaluate drug safety.Reference Pasquali, Lam, Chiswell, Kemper and Li ^{16 – 18}

Figure 1

Time line depicting recent regulatory initiatives to encourage paediatric drug study in the United States and Europe.

Measuring our successes and failures

With such significant changes in the paediatric clinical trials landscape, we sought to evaluate progress within the field of paediatric cardiology. How does our trial infrastructure and volume compare with our adult colleagues or with other paediatric sub-specialties? What types of trials are we conducting? What are the important drivers of trial design and conduct, and, most importantly, are we optimally advancing the evidence base in paediatric cardiology? To address these questions, we will focus on the US clinical trials landscape as the US Congress has established several mechanisms to evaluate progress. First, was the creation of a clinical trials registry: ClinicalTrials.gov is a searchable database that was mandated by Congress under the 1997 Food and Drug Administration Modernization Act and was made publically available in February of 2000.Reference Aisenberg ^{19 , 20} ClinicalTrials.gov includes information on trial design, study cohort, outcome measures, trial timeline, and, more recently, trial results. In 2005, the International Committee of Medical Journal Editors began requiring trial registration as a condition for publication, and in 2007 the US Congress began requiring registration of all clinical trials conducted in the United States of America. ^{9 ,} Reference De Angelis, Drazen and Frizelle ²¹ These actions have greatly increased trial registration; there are now >180,000 registered trials on ClinicalTrials.gov (Fig 2). A second mechanism to evaluate progress in paediatric cardiovascular clinical trials is the US Food and Drug Administration’s “New Pediatric Labeling Information Database”. ²² This public database was mandated by Congress in 2007, and it includes a listing of all trials conducted under the auspices of recent legislative efforts, as well as the reviews of these trials and the associated labelling changes. Together, ClinicalTrials.gov and the Pediatric Labeling Information Database include a wealth of information that can provide important insights into paediatric cardiovascular trials and their outcomes.

Figure 2

Clinical trials registered on ClinicalTrials.gov and associated milestones. FDAMA=The Food and Drug Administration Modernization Act; ICMJE=International Committee of Medical Journal Editors; NIH=National Institutes of Health; NLM=National Library of Medicine.

ClinicalTrials.gov

Numerous publications have used the ClinicalTrials.gov database to evaluate the clinical trials landscape. Califf et al evaluated adult cardiovascular trials in comparison with oncology and mental health trials.Reference Califf, Zarin, Kramer, Sherman, Aberle and Tasneem ²³ Over a 3-year span from October, 2007 to September, 2010, 3437 adult cardiovascular trials were registered. Significantly, US National Institutes of Health-sponsored trials performed substantially better across all trial quality metrics when compared with industry or other sponsor sources. In a follow-up to this assessment, Pasquali et al evaluated the paediatric clinical trials landscape.Reference Pasquali, Lam, Chiswell, Kemper and Li ¹⁶ In this analysis, which spanned from July, 2005 until September, 2010, 5035 trials restricted to children and adolescents (aged <18 years) were registered. Paediatric trials were dominated by infectious disease trials, which comprised ~23% of all registered trials (Fig 3). Other paediatric specialties with a relatively larger volume included the following: mental health/psychiatry (~13%), neurology/anaesthesia/pain (~11%), pulmonary (~10%), endocrine/metabolic (~10%), and gastrointestinal/nutrition (~7.5%). In comparison, paediatric cardiology trials represented a relatively small subset of the overall trial landscape (~4.5%); the only sub-specialties with significantly fewer trials were haematology, dermatology, and nephrology.

Figure 3

Paediatric trials registered on ClinicalTrials.gov (September, 2005–October, 2010). AI = allergy/immunology; GI = gastroenterology; ID = infectious diseases.

Paediatric cardiovascular trials registered on ClinicalTrials.gov

Using the same database as Pasquali and Califf, we evaluated the subset of paediatric cardiovascular trials.Reference Hill, Chiswell, Califf, Pearson and Li ¹⁷ Overall, 213 paediatric cardiovascular trials (aged <18 years) were registered between September, 2005 and October, 2010. After manual review, we identified an additional 71 trials that also included adult patients (age ⩾18 years) but that we judged to have a primary paediatric cardiovascular focus, examples include the US Medtronic Melody valve trial and the Pediatric Heart Network trial of losartan versus atenolol for Marfan syndrome. Paediatric cardiovascular trials had a median (interquartile range) trial enrolment of 65 (36, 186) patients and only four registered trials had a projected enrolment of >1000 study patients. The median trial duration was 2.2 (interquartile range: 1.4, 3.3) years. Overall, 68% of trials used a drug/biologic intervention, 12% were device interventions, and 10% were behavioural interventions.

In terms of specific trial focus, collectively, hypertension, dyslipidaemia, obesity, and pulmonary hypertension trials comprised >40% of all trials (Fig 4). These trial subsets also appeared to dominate funding priorities; hypertension and obesity trials represented 61% of all National Institutes of Health-funded trials, whereas hypertension, pulmonary hypertension, and dyslipidaemia trials accounted for 49% of all industry-funded trials. Device trials accounted for an additional 15% of industry-sponsored trials. Overall, 44% of all registered paediatric cardiovascular trials identified had industry or National Institutes of Health sponsorship. Over a 3-year span (September, 2007–October, 2010), 24 paediatric cardiovascular trials were sponsored by the US National Institutes of Health and 69 were sponsored by the industry. In contrast, over the same time period, 295 adult cardiovascular trials and 149 paediatric mental health trials were sponsored by the National Institutes of Health, and 2365 adult cardiovascular trials and 708 paediatric infectious disease trials were sponsored by the industry. Importantly, paediatric cardiovascular trials generally did well in terms of quality metrics with 75% reporting randomisation, 51% using blinding, and 54% reporting the use of a data monitoring committee. Similar to adult trials, the most important factor associated with the conduct of a high-quality trial, with a randomised and blinded design, was sponsorship by the US National Institutes of Health – multivariable odds ratio, 1.9 [95% CI, 1.5–2.4] when compared with industry sponsorship.Reference Hill, Chiswell, Califf, Pearson and Li ¹⁷

Figure 4

Paediatric cardiovascular trial focus and funding sources. NIH = national institutes of health; PDA = patent ductus arteriosus; CPR = cardiopulmonary resuscitation.

Heart failure trials

With the primary focus on paediatric heart failure and heart transplant at the 2015 Daicoff summit, we subsequently used the search terms “heart failure” or “heart transplant” to interrogate ClinicalTrials.gov for all paediatric trials (enrolling patients aged <18 years). These trials were downloaded and manually reviewed to identify trials with a primary paediatric cardiovascular focus. A search from 1 July, 2005 to 1 January, 2015 yielded 212 trials; however, the majority were excluded due to a primary adult focus or because the trials were withdrawn or terminated. We identified only 10 active (n=6) or completed (n=4) paediatric heart failure/heart transplant trials in this 10-year period. These trials are summarised in Table 1. The 10 trials were sponsored by the industry (n=8) or the National Institutes of Health (n=2); nine represent drug trials including five with a safety end point and five with a pharmacokinetic end point. Only two of the drug trials assessed efficacy end points and both were National Institutes of Health-sponsored trials: the Pediatric Heart Network Infant Single Ventricle trial and a National Institutes of Health-sponsored trial of diltiazem in patients aged between 5 years and 39 years with early signs of hypertrophic cardiomyopathy. Furthermore, one trial, the EXCORÂ^® Pediatric Ventricular Assist Device trial, was an industry-sponsored trial with a safety and pseudo-efficacy end point, compared with historical controls. For these 10 trials, trial enrolment ranged from 10 to 230 patients with only two enrolling >100 patients. Of the four completed trials, listed completion dates ranged from January, 2006 to September, 2013. Despite all the trials being completed for over a year, only two of these trials have published results identified on ClinicalTrials.gov or Pubmed.

Table 1

Paediatric heart failure or heart transplant trials registered on ClinicalTrials.gov 2005–2014.

NIH (PHN)=National Institutes of Health (Pediatric Heart Network); PK=pharmacokinetics; RCT=randomised control trial

The Food and Drug Administration Pediatric Drug Labeling Database

ClinicalTrials.gov provides a meaningful overview of the clinical trials landscape; however, a major limitation is that it is difficult to use this database to assess the impact of trials on the overall evidence base. Although there is no perfect metric for evaluating this outcome, changes to the drug label represent a reasonable surrogate of new evidence. The US Food and Drug Administration Labeling database tracks labelling changes for paediatric drugs. ²² As of 14 November, 2014, the drug database documented 489 studies that have been completed for paediatric agents. Of these, 28 (5.1%) represent cardiovascular agents including 16 anti-hypertensive agents and eight lipid-lowering agents including seven statins. The remaining four drugs are carvedilol, sildenafil, sotalol, and clopidogrel (Table 2). All the eight lipid-lowering agents have been studied for heterozygous familial hypercholesterolaemia in adolescents and all have resulted in a new labelled indication for the drug – that is, have demonstrated efficacy. The anti-hypertensive trials have led to 10 new labelled indications (63% success rate). None of the remaining four drugs have demonstrated efficacy in the paediatric trials; three were negative trials, whereas the sotalol trialReference Saul, Ross and Schaffer ^{24 ,} Reference Saul, Schaffer and Karpawich ²⁵ did not evaluate an efficacy end point, instead focussing on drug kinetics.

Table 2

Cardiovascular drugs with studies performed for paediatric exclusivity that have resulted in labelling changes.

*Irbesartan trials remain unpublished and details are not readily available

What can we learn from the negative trials?

• ∙ Hypertension trials: In an insightful analysis, Benjamin et al found that the successful hypertension trials used large differences in the dose ranges of the drugs studied (20- to 32-fold), with little or no overlap between low, medium, and high doses, whereas failed trials used overlapping dose ranges, which made it more difficult to detect a dose–response effect.Reference Benjamin, Smith and Jadhav ²⁶ Successful trials also provided paediatric formulations and used diastolic blood pressure, which tends to demonstrate less variability than systolic blood pressure, as the primary study end point.

• ∙ Carvedilol: These studies failed to demonstrate improved outcomes in children with cardiomyopathy with either low- or high-dose carvedilol when compared with placebo.Reference Shaddy, Boucek and Hsu ²⁷ The investigators noted several important factors that may have contributed to the negative trial outcome and they can serve as valuable lessons for future trials: relative to adults, patients – particularly younger patients – with heart failure had a higher than anticipated rate of spontaneous improvement. As a result, the trial was relatively underpowered; the study end point was a composite heart failure outcome with three levels of assessment – improved, no change, worsened. Assessing three levels requires more power and compounded the noted problems with sample size; there were several signals suggesting a mixed response: children with a systemic right ventricle demonstrated a trend towards worsening function with carvedilol, whereas those with a single left ventricle demonstrated a trend towards improvement, and younger children were more likely to improve than older children; and, finally, relative to adults, children demonstrated more rapid drug clearance and consequently trough concentrations of carvedilol were relatively lower. Taken together, the findings from this trial are often viewed as inconclusive in patients with a systemic left ventricle. A show of hands at the Daicoff summit suggested that most heart failure providers still use carvedilol off-label in children with left heart failure.

• ∙ Sildenafil: These trials have been the source of much debate in the paediatric literature. Initial pharmacokinetics trials were completed, but to our knowledge the data have not been published in the medical literature and are available only through the Food and Drug Administration’s clinical pharmacology reviews. ²⁸ The initial efficacy trial did not demonstrate improved exercise tolerance when comparing low-dose sildenafil with placebo in children with pulmonary hypertension.Reference Barst, Ivy and Gaitan ²⁹ In the long-term extension trial, children randomised to high-dose sildenafil had increased mortality when compared with low-dose sildenafil.Reference Barst, Ivy and Gaitan ^{29 ,} Reference Barst, Beghetti and Pulido ³⁰ Similar to carvedilol, there was a mixed signal with worse outcomes in children with idiopathic pulmonary hypertension when compared with those with CHD-associated pulmonary hypertension, and the increased mortality effect seen primarily in older children. The European Medicines Agency interpreted the trial results in the context of historically poor outcomes for children with pulmonary hypertension, noting that children receiving low-dose sildenafil had improved survival when compared with historical controls. ³¹ They approved low-dose sildenafil for the treatment of paediatric pulmonary hypertension. In contrast, the Food and Drug Administration did not approve any dose of sildenafil and went one step further by placing a safety warning on the drug label. ³²

• ∙ Clopidogrel: This trial evaluated clopidogrel in addition to standard therapy – aspirin for 87% of trial patients – for the prevention of shunt thrombosis and associated morbidity in neonates and infants with a systemic-to-pulmonary artery shunt.Reference Wessel, Berger and Li ³³ There was no additive benefit with clopidogrel, and therefore there is no paediatric indication for the use of clopidogrel in children; however, the drug label specifically notes that the negative study may reflect that the majority of study patients were receiving concomitant aspirin therapy.