Study shows that almost half of pediatric trials are not finished or published
Tuesday, November 1, 2016
As Research Practitioner highlighted earlier this year, clinical research results have been disclosed late or not at all at least 95% of the time since reporting of results from human studies to the federal government’s ClinicalTrials.gov database became mandatory in 2008.1 Most of these trials, however, use adult subjects. Researchers at Boston’s Children Hospital in Massachusetts decided to examine the reporting of pediatric study results and found that almost half of the studies had been discontinued or not published.
Pediatric trials may be particularly vulnerable to these outcomes, say study authors Natalie Pica and Florence Bourgeois. Pica is a clinical fellow in pediatrics and Bourgeois is an assistant professor of pediatrics at Harvard Medical School and a member of the Division of Emergency Medicine and Computational Health Informatics Program at Boston Children’s Hospital. “[Pediatric trials] face unique challenges in terms of concerns around testing interventions in children and the logistics of recruiting and consenting research subjects in collaboration with parents and caretakers. In addition, there has historically been more limited funding allotted to pediatric research, both by industry and nonprofit sponsors, posing additional challenges to the successful conduct of trials,” they say.2
The researchers conducted a cross-sectional study of randomized pediatric clinical trials registered in ClinicalTrials.gov. They limited their analyses to randomized trials studying children (birth–age 17 years) and registered between January 1, 2008, and December 31, 2010, and selected trials that were completed or had been discontinued by December 31, 2012. They then searched for related peer-reviewed publications through September 1, 2015. When no publication could be found, they sent inquiries to study investigators and sponsors via email.3
Pica and Bourgeois identified 559 randomized pediatric clinical trials that met inclusion criteria for their analysis. Their findings included:3
- Of the 559 trials, 104 (19%) were discontinued early. Two-thirds of these had already enrolled participants. The researchers say that poor recruitment and problems with the conduct of the trial were among the most commonly reported reasons for trial discontinuation.
- Of the 455 completed trials, 136 (30%) remained unpublished after an average of 58 months post-completion. (Forty-two of these, or 31%, did post results to ClinicalTrials.gov.)
Of the 104 discontinued trials, 39% were sponsored by industry and 55% by academic institutions. (The rest were funded by other sources.)
- Two years after trial completion, academia-sponsored trials accounted for 30% of unpublished trials, and industry-sponsored trials for 63%. Three years after trial completion, academia-sponsored trials accounted for 23% of unpublished trials, and industry-sponsored trials for 70%.
- In a multivariate analysis, the likelihood of nonpublication was more than double for industry-sponsored trials two years after completion (odds ratio, 2.21) and more than triple three years after completion (odds ratio, 3.12). Among these unpublished trials, 42 (30.8%) had results posted in the registry.
- Overall, more than 8,000 children were enrolled in trials that were never completed, and more than 69,000 children (27% of the total study population among completed trials) were enrolled in completed trials that were never published.
A number of trials were discontinued for reasons considered informative, including preliminary safety and efficacy findings or changes in the standard of care that occurred after the trial had been initiated, the researchers say. “Such termination likely prevents further wasted resources and may be unavoidable at a certain baseline rate. However, there may be opportunities to reduce non-informative trial discontinuation, such as poor patient accrual and technical or logistical issues with trial conduct.” The rate of discontinuation of pediatric trials (19%) was comparable to rates found in adult populations (21-25%), they add, indicating that the “potential challenges encountered with pediatric patient recruitment do not appear to increase the odds of trial discontinuation.”2
The nonpublication rate of 30% for the pediatric trials is consistent with other studies looking at nonpublication across a range of trial types, Pica and Bourgeois say. “The nonpublication of trial findings represents a violation of the ethical imperative to share results of trials that involve human subjects and also introduces publication bias into the medical literature,” the authors say. “Trial nonpublication is particularly concerning given the limited availability of volunteers for clinical trials and the high rates of trial termination due to difficulties in participant accrual.”
The study shows that trial sponsors were an important determinant of these outcomes, with trials funded by industry less likely to be discontinued but more likely to remain unpublished 24 and 36 months after trial completion.2 “This may be related to additional financial and human resources available in industry-funded trials, such as research coordinators to manage patient recruitment or technical infrastructure to facilitate trial conduct,” the authors say. “For academic trials in particular, investigators and research oversight committees should be accountable for ensuring that clinical trials are feasible and have the material and human resources available to achieve the proposed goals.”
Nonpublication of these trials has consequences to the research community, according to the study authors. “The Declaration of Helsinki, which is the central document governing regulation of human subjects research, states that investigators are responsible for the public dissemination of trial results involving human participants, regardless of the findings,” they say. “There is some evidence that trial registration has contributed to an increase in the publication of trials with negative results, thus curbing publication bias related to preferential reporting of positive findings.”2
Similar results in 2012
Back in 2012, Pediatrics published an article that was also critical of how information was not being published from pediatric clinical trials. Tatyana Shamliyan and Robert Kane, then of the University of Minnesota School of Public Health in Minneapolis, wanted to examine registration, completeness, and publication of studies involving children. They looked at publication in peer-reviewed journals for randomly selected National Institutes of Health (NIH)–funded studies from 2000 through 2010 and for randomly selected completed studies.4
They found these results:
- Of 3,428 closed studies involving children identified in ClinicalTrials.gov, 2,385 (70%) were completed, 28 (0.8%) suspended, 152 (4.4%) terminated, and 38 (1.1%) withdrawn.
- The proportion of non-completed studies (terminated and suspended) increased linearly by 186% between 2001 and 2009, from 1.9% to 8.4%.
- Of the 152 terminated studies, 48 did not report reasons for termination, 21 cited safety concerns, and 83 cited poor recruitment or other administrative reasons.
- Only 29% of completed studies were published. Publication that did occur was an average of two years after study completion. Completed interventional studies were published more often than observational studies. Completed industry-funded studies were published less often than studies funded by the NIH. Registered NIH-funded trials were published more often than unregistered.
Reporting of noncompleted studies is especially important if the studies were terminated because of detected harms from the treatments, the authors say in their conclusion.4
Although the literature includes extensive discussions of ethics and regulations related to research involving children, completeness and reporting of results have been neglected. Studies involving children should always post reasons for termination or suspension on ClinicalTrials.gov. Many of the terminated and completed studies we examined lasted more than two years, during which time children experienced important outcomes, including harms. Those outcomes should be available for analysis.”
Posting study results in ClinicalTrials.gov provides access to research findings not otherwise available to the public, they continue, but “the credibility of the posted protocols and findings depends on the commitment of investigators to submit complete and accurate data.” The results of only 9% of all completed studies and 7.5% of Phase II through IV clinical trials involving children were posted on ClinicalTrials.gov, they say. Only 24% of the studies that posted results were also published. “Policy should obligate principal investigators of all clinical trials involving children to post results on ClinicalTrials.gov.”
In an accompanying editorial, Scott C. Denne, professor and associate chair of pediatrics for clinical and translational research at Indiana University School of Medicine in Indianapolis, made a call for action. “At present, the results of most clinical studies of children are unavailable to the pediatric research community and the public. As a consequence, trials may be unnecessarily repeated, and the information cannot be used to guide therapy,” he says. “We have made great progress toward including children in research, and thousands of children have participated in clinical investigations. One of the most important obligations to the children and families who have willingly enrolled in trials is to ensure that their participation can benefit all children. Only timely, complete, and readily available clinical trial results can meet this obligation. We have a viable mechanism (ClinicalTrials.gov) to post trial results, but have fallen far short of the goal. Addressing this deficiency will require a renewed commitment by clinical investigators, the NIH, the pharmaceutical industry, and the FDA. It is time for urgent action.”5
Researchers push back
Researchers also spoke out about the 2016 article — some in defense of the problems relating to publishing trial information. “Maybe the results don’t show what the investigator wants and they move on,” says Joseph S. Ross, an assistant professor in the Section of General Internal Medicine at the Yale University School of Medicine in New Haven, CT. “But more often people are busy and people don’t focus enough time and attention on getting those results out.” He considers this an ethical lapse. “When you do a clinical study and you’re asking patients to participate and subject themselves to a risk, in order to inform science and generate knowledge, you have an ethical obligation to disseminate those results to the wider scientific community.”6
Along with some of his colleagues, Gregory L Kearns, president of the Arkansas Children’s Research Institute, senior vice president and chief research officer for Arkansas Children’s Hospital, and a professor of pediatrics at the University of Arkansas for Medical Sciences, took issue with part of Ross’ comments. “Having published many clinical trials, we found this assessment is unfair to the researchers and fails to identify likely causes,” they write.7
Several practical issues make publication of pediatric clinical trials difficult, they explain. These issues include:
- Pediatric trials are often small, especially when compared to many adult studies, which “detracts from their perceived scientific and societal impact and negatively affects publication decisions.”
- Trials involving children are more likely to be published in pediatric journals as opposed to more widely read mainstream biomedical journals. “This is especially true for studies reporting negative results, a factor known to be associated with editorial bias,” Kearns and colleagues say.
- Pediatric trials are often conducted long after adult approval when “off-label” pediatric treatment is frequent, which reduces parent, practitioner, and investigator enthusiasm contributing to small studies.
- Pediatric studies may be conducted to satisfy a regulatory requirement rather than to generate new knowledge to improve pediatric therapy, reducing both investigator and publisher enthusiasm, again contributing to small and hard-to-publish studies.
- Finally, clinical trials initiated after September 27, 2007, which meet the FDAAA 801 definition of an applicable clinical trial, conducted at one or more sites in the United States or those supported by funding from NIH, must register at ClinicalTrials.gov. “While this mechanism does make information from specific trials generally accessible, it is not a substitute for the proven, time-honored peer review publication process,” they say. “In conclusion, child health researchers are by and large hard working, ethical, and highly motivated professionals who are committed to improving the health and welfare of children through the process of discovery, which includes conducting and publishing research to the highest standard. The implication that the publication gap is due to lack of effort is, in our view, neither accurate nor fair.”
Benefits of federal legislation
Since children have historically been underrepresented in clinical trials compared with adults, a number of FDA policies aim to incentivize and increase the study of interventions in pediatric populations, say Pica and Bourgeois. These include the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act, which have been credited with increasing the number of pediatric drug trials and the number of drug labels that contain pediatric safety and efficacy information. “Our findings indicate that once trials are initiated, additional focus is needed to maximize the knowledge gain from pediatric trial participation.”2
Mary Dianne Murphy, pediatrician and director of FDA’s Office of Pediatric Therapeutics, pointed out in a comment to the article that the legislation also requires FDA to post its reviews of the medical, pharmacology, and statistical data submitted for pediatric trials. These reviews can be found on FDA’s website at http://www.fda.gov/ScienceResearch/SpecialTopics/PediatricTherapeuticsResearch/default.htm. Murphy says that FDA has now reviewed pediatric studies for more than 630 products. “There is an enormous amount of information to be learned from both the failed and successful trials,” she says.8 “Under the Best Pharmaceutical for Children legislation, even ‘failed’ trials may result in the product receiving additional marketing exclusivity, IF they have performed the trials in the manner requested by FDA. Ongoing analysis of these trials has revealed errors in our assumptions about the similarity and differences between adults and children in both the pathophysiology of some diseases and the responses to therapies administered as treatment.
“We agree with the authors that all data obtained from children who are participating in a trial should be publicly available in order to advance our knowledge, even if the trial was not completed or failed to demonstrate the desire or anticipated response,” Murphy says. “These data are actually sometimes the most informative information we obtain. They challenge our preconceived ideas or assumptions and advance our knowledge about possible differences between the pediatric and adult manifestations of disease and responses to therapy.”
Other possible solutions
A number of legislative initiatives have been implemented to increase the study of interventions in children, says Bourgeois.3 “Now we need to make sure that the proper resources are in place to ensure that information gleaned from these studies reaches the scientific community.” One initiative she and Pita cited in the article is RIAT (Restoring Invisible and Abandoned Trials). RIAT invites researchers with unpublished trials to either commit to publish within a year or provide public access to their data, allowing independent investigators to become “restorative authors.”
RIAT was proposed in a June 2013 BMJ article by Peter Doshi and four colleagues. At that time, Doshi was a postdoctoral fellow at Johns Hopkins School of Medicine in Baltimore, Maryland, and is now an assistant professor of pharmaceutical health services research in the School of Pharmacy at the University of Maryland and associate editor at the BMJ.9 PLOS Medicine also endorsed the proposal. “It’s hard to reanalyze others’ data,” says Pica, “but this may be a useful mechanism to make sure that findings from completed trials are disseminated in the medical literature.”
No matter what the focus of these trials, Pica says, children are taking some inherent risk by participating. “We owe it to those participants to conduct those trials ethically and disseminate that information.”10
- Piller C. French debacle renews concern about clinical trial secrecy. STAT Jan. 20, 2016. Available at http://www.statnews.com/2016/01/20/french-clinical-trial-debacle.
- Pica N, Bourgeois F. Discontinuation and Nonpublication of randomized clinical trials conducted in children. Pediatrics Published online August 4, 2016. Available at http://pediatrics.aappublications.org/content/early/2016/08/02/peds.2016-0223.
- Nearly half of pediatric clinical trials go unfinished or unpublished. Boston Children’s Hospital. August 2016 Available at http://www.childrenshospital.org/news-and-events/2016/july-2016/nearly-half-of-pediatric-clinical-trials-go-unfinished-or-unpublished.
- Shamliyan T, Kane R. Clinical research involving children: Registration, completeness, and publication. Pediatrics 2012;129:1291-1300.
- Denne SC. Pediatric clinical trial registration and trial results: An urgent need for improvement. Pediatrics 2012:129:1320-1321.
- Harris R. Medical studies involving children often go unpublished. NPR August 2, 2106. Available at http://www.npr.org/sections/health-shots/2016/08/04/488708038/medical-studies-involving-children-often-go-unpublished.
- Kearns GL, Rieder M, Ward, R. Children’s research often goes unpublished. Pediatrics comment section October 11, 2016. Available at http://pediatrics.aappublications.org/content/early/2016/08/02/peds.2016-0223.comments#children%E2%80%99s-research-often-goes-unpublished-.
- Murphy MD. Re: Discontinuation and Nonpublication of randomized clinical trials conducted in children. Pediatrics comment section August 23, 2016. http://pediatrics.aappublications.org/content/early/2016/08/02/peds.2016-0223.comments#children%E2%80%99s-research-often-goes-unpublished-.
- Doshi P, Dickersin K, Healy D, et al. Restoring invisible and abandoned trials: A call for people to publish the findings BMJ 2013;346:f2865
- Mullin E. Pediatric clinical trials are often abandoned, unpublished. Forbes August 5, 2016. Available at http://www.forbes.com/sites/emilymullin/2016/08/05/clinical-trial-data-in-children-is-going-unpublished/#662a5ea70b7b.
By Sue Coons, MA
This article was reprinted from Research Practitioner, Volume 17, Number 6, November-December 2016.