Peer-Reviewed Publication of Clinical Trials Completed for Pediatric Exclusivity FREE

For a product to be marketed in the United States, the sponsor must submit adequate and well-controlled trials that demonstrate the efficacy and safety of the product when used as intended to the US Food and Drug Administration (FDA). These trials are the basis of the labeling or package insert instructions that are provided for each product that is approved by the FDA. Children are usually not included in most product submission studies and therefore, the data on dosing, efficacy, and safety that are available for adults are not usually available for pediatric patients. Other data may be available but are often not from the same type of rigorous clinical trials. Historically, 75% of drug products have insufficient labeling information for pediatric dosing, safety, or efficacy.

Inadequate dosing and safety information places children at risk for adverse events and denies them potential therapeutic benefits. Physicians who care for children have therefore, been forced to either withhold treatment shown to be effective in older patients or provide drugs to children in whom the dose, efficacy, and safety have not been studied. This prescription practice is known as off label use because there is not adequate pediatric information in the labeling. This off-label use may result in benefit, no effect, or harm, depending on how much other information about use of the product in the pediatric population is available. The lack of information has had a negative impact on pediatric therapeutics, including reliance on anecdotal practice patterns and adaptation of data from adult trials that may not be applicable to children.

Congress passed the Food and Drug Administration Modernization Act in 1997. One component of this act is the authorization of a pediatric exclusivity process, whereby the study of therapies used in children, and potentially of use in pediatrics, is encouraged via a 6-month marketing protection extension incentive. The marketing protection extension, pediatric exclusivity, is in return for performing studies specified by the FDA. The Best Pharmaceuticals for Children Act of 2002 renewed the incentives for the study of marketed drugs, and the pediatric exclusivity program receives broad support from pediatricians, professional societies, and other public health advocates¹; however, the program is not without controversy or critics. Critics have asserted that the cost of the program to the public will exceed $14 billion as a result of the sole marketing protection extensions² (eg, extended patent protection) and the resultant delay of generic products into the US market.

The pediatric exclusivity program has been successful from many perspectives, including labeling, with over 100 labeling changes to date. However, the subsequent dissemination of results in the peer-reviewed medical literature has not been previously quantified. Because few pediatric studies are performed for products primarily approved and marketed for adults, it is important that the information obtained from such studies be readily available. One standard for dissemination of human experimentation results is publication in a peer-reviewed journal.³ We evaluated the frequency of publication of studies completed for pediatric exclusivity. We hypothesized that publication would be incomplete and that positive labeling changes would be associated with increased probability of publication.

The unit of observation for this study was the clinical trial. The cohort of clinical trials included any informative human study (pharmacokinetic, safety, efficacy, etc) that we identified through the “written request” mechanism of the pediatric exclusivity program. The written request, generally issued by the FDA prior to initiation of pediatric exclusivity studies, contains required elements of the requested studies, including indication, number of studies, sample sizes, trial design, and age ranges to be studied. The focus of these studies is a combination of furthering our knowledge of the dosing, safety, and efficacy of the drugs in children. The results of the studies comprise much of the final study report that is submitted to the FDA. It is noteworthy that marketing exclusivity is extended regardless of the outcome of the trials requested by the FDA, provided that the companies fairly respond to the terms of the written request. From the written requests, final study reports, and the FDA's regulatory actions on the submissions, we recorded the basic elements of design and subsequent labeling changes for each product. All studies completed in response to a written request and submitted to the FDA are evaluated by the agency. Thus, this cohort captures 100% of the studies evaluated as part of the pediatric exclusivity program within our time frame.

The primary independent variable was based on the labeling change that resulted from the exclusivity submission. Labeling change categories included positive labeling changes, negative labeling changes, submission completed but no labeling change, submission/application withdrawn, or product withdrawn from the market. Examples of positive labeling changes included “safety and effectiveness established” and “approved for use in children”. Examples of negative labeling changes included “no meaningful clinical activity”, “black box warning”, and “increased mortality reported in the product compared to placebo”. We collapsed the categorical labeling change variable into the primary independent variable. If the labeling change was positive, we categorized the outcome as positive; we otherwise categorized the outcome as negative. The categorization of the labeling changes was adjudicated by the authors affiliated with the FDA. Two authors (D.K.B. and J.S.L.) first categorized the labeling changes. Label changes were then categorized by 3 authors (L.M., D.A., and R.R.). Differences were then discussed and adjudicated (D.A., D.K.B., M.D.M., J.S.L., L.M., and R.R.). Reconciliation was required for 2 products.

Drug labeling changes also were classified with respect to public health impact. Labeling changes were classified as “key labeling changes” if the studies resulted in substantive dosing changes, new safety information, or lack of efficacy in phase 3 testing. Study type was classified as follows: efficacy, dose-ranging or multi-dose pharmacokinetics, single-dose pharmacokinetics, or safety. Race and ethnicity were not uniformly provided for each study, but most of the trials conducted have submitted the fraction of children enrolled who were white. These data are reported as a marker of racial and ethnic diversity of enrolled children. We recorded the annual sales⁴ for each product for the most recent available year that the product had sole marketing protection in the United States. The number of centers at which each trial was conducted was transformed into a categorical variable (< 7 centers, 7-17 centers, 18-34 centers, and > 34 centers).

The primary outcome was publication of the main study results in a peer-reviewed journal. If the results of 2 or more studies were combined into 1 publication,⁵ then all studies with data reported in the paper were counted as published. If data from a study was combined with data from nonexclusivity trials (eg, a population pharmacokinetic study), then the study was counted as published. If studies of 2 products were performed in the same trial and the trial results were published,⁶ then both studies were counted as published. If we were able to determine if data from a study were nested within an article that reported results from different patient populations,⁷ we counted the study as published.

MEDLINE and EMBASE were searched for published studies. For MEDLINE, we used 3 separate search strategies to obtain publication status. One author searched MEDLINE (J.S.L.), entered the generic name of the product, and limited the search strategy to all child (0-18 years), 1998-2005, and English language. Each abstract was read and compared with the written request or final study report. If the abstract was a potential match, the article was obtained and read. A second author (D.K.B.) entered the product's generic name, and limited the search to 1998-2005, English language and ages of trial participants from the written request and/or final study report. A third author (P.B.S.) used key words from the study design provided by the written request and the generic name. This final strategy allowed for the capture of manuscripts prior to 1998. We also searched EMBASE using the drug name and ages of participants (D.K.B.). Each search strategy had high sensitivity; 6 articles were found by only 1 of the strategies. When an article matched, we recorded the 2004 journal impact factor.⁸ Finally, a study coordinator at Duke University requested publications (including those already published, in press, or submitted) from studies conducted for pediatric exclusivity from each company. This resulted in no additional publications. We did not include publications limited to abstracts or publications in trade journals because it was our primary aim to assess ready availability of results to the practicing physician. The analysis was limited to studies for which the data were submitted to the FDA Pediatric Exclusivity Board by December 1, 2004 because of the delay between completion of study, manuscript preparation, and publication.

Reported P values and 95% confidence intervals (CI) were 2-tailed. Odds ratios (OR) and 95% CIs were derived from logistic regression modeling using STATA 8.2 (STATA Corp, College Station, Tex). We used forward selection logistic regression, and the maximum number of variables in the model did not exceed the variables presented in the final model. We limited the number of variables in accordance with previously published regression methods.⁹ We repeated the multivariable analysis using 3 models: a parsimonious model that included only those variables that were associated (P< .05) with publication in forward selection, a model that included variables associated with publication and adjusted for year of submission, and a model that included variables associated with publication and adjusted for year of submission and log-sample size (of children enrolled).¹⁰ Because the results of all 3 models were similar, we present only the parsimonious model. Variables that were retained in the forward selection were the primary independent variable and dummy variables assigned to study type. Variables that were analyzed in forward regression but were not retained included sample size and log-sample size, year of submission of data to the FDA, number of centers (analyzed as a continuous and as a categorical variable), fraction of children enrolled who were categorized as white race, and annual sales of the drug in the latest year of patent protection.⁷

Each study included in this analysis was performed under good clinical practice and underwent institutional or ethics board review at the sites where it was completed. This study is an analysis of publicly available data; we did not access individual patient-level data for this research. We presented the project and the information we were collecting to the Duke University Medical Center Institutional Review Board and received exemption from review for this analysis.

Between January 1, 1998 and December 31, 2004, data from 115 therapeutic agents were submitted to the FDA Pediatric Exclusivity Board. The number of studies for each agent ranged from 1 to 8; 253 studies were submitted (Table 1). The sample size for each study was variable, from 8 children in a single-dose pharmacokinetic study to 27 065 in an open-label safety study; 23% of studies enrolled fewer than 30 children, the median enrollment was 103, and 2 studies enrolled more than 1000 children.

Only 113/253 (45%) of the studies were published in peer-reviewed journals. A positive labeling change was observed for 127/253 (50%) of studies. Efficacy studies and studies that resulted in a positive labeling change were more likely to be published (Table 2). These associations remained strong in multivariable analysis (Table 3).

Annual sales of the drug products and number of centers that participated in enrollment were not associated with subsequent publication. These variables were explored as continuous, categorical, and dummy variables. The number of centers was missing from a large number of observations because center reporting was not required prior to 2002. However, at least 73 studies enrolled children in countries outside of the United States including eastern and western Europe, Russia, Latin America, and sub-Saharan Africa. Neither race nor clinical therapeutic area was associated with subsequent publication.

Data for the studies were submitted over the course of 7 years (1998-2004), but year of submission of data was not associated with subsequent publication. We further explored the relationship between the time that the data were submitted to the exclusivity board of the FDA and subsequent publication (Figure). The median time to publication was 16 months after the data were submitted to the FDA; 75% of studies were published within 24 months of submission, and 90% were published within 36 months. Only 3 studies that were published were delayed more than 48 months after submission of the data to the FDA. Studies could be submitted for publication prior to submission of the data to the agency; in fact, 27% were published prior to submission of the data to the FDA. Of note, 202/253 studies (80%) were submitted prior to December 2003: specifically, at least 80% of the studies for this analysis were completed more than 30 months prior to our evaluation, and all studies were completed (enrollment finished, data analyzed, and data submitted) more than 18 months prior to our evaluation.

Although all studies for several products were published,^5,7,11- 23 several products with substantial safety concerns²⁴ were not published at the time of this writing. The relationship between lack of a successful labeling change and subsequent publication was not absolute. Many studies were published that were given a negative labeling change or not granted a labeling change.^16,25- 28 The peer-reviewed journals that accepted the publications were high quality. The mean impact factor for journals that accepted publications, was 6.

There were 100 clinical trials associated with a key labeling change, but only 37 were published. There were 48 trials that did not result in a labeling change (40 from completed submissions and 8 associated with products that were withdrawn from the market or the application was withdrawn), and only 19/48 (40%) were published. Thus, 3804 children were enrolled in 29 clinical trials for 16 products resulting in no labeling change and no dissemination of results.

We have found that studies completed for pediatric exclusivity are often not published in the peer-reviewed literature. It is important to note that a product may be granted pediatric exclusivity even if the product fails to show effectiveness or obtain FDA approval for marketing. The rationale behind this approach is that the information collected in a well-controlled and designed trial is important even if it fails to demonstrate effectiveness. Because so few pediatric studies are conducted for therapeutics, a well-constructed effort to answer a question is seen as deserving of the exclusivity irrespective of the ultimate answer. The primary goal of pediatric exclusivity is to provide an incentive to conduct studies in children that will improve the labeling of products and thereby improve public health. The pediatric exclusivity program has been successful in reinvigorating clinical research involving drugs used in children and improved pediatric labeling^29- 30; but the research has not been consistently disseminated into the peer-reviewed medical literature. Peer-reviewed publication is crucial to public health benefit because such publication often is the primary means of notifying physicians of information that can update their knowledge of therapeutics and may change their prescribing approach. Our findings are consistent with prior investigations of research and subsequent peer-reviewed publications.^31- 33

Clinical research is an activity involving human participants that contributes to broader-based knowledge.³⁴ An important first step is the submission of data to the FDA for review and subsequent authorization of labeling changes if the data so warrant. However, failure to publish pediatric research in a venue in which the clinical community can study and debate the findings can pose a public health risk. Selective serotonin reuptake inhibitor agents and propofol are drugs in which this risk was particularly evident. Numerous ethical statements from foundation documents^34- 35 and professional organizations³ have emphasized that publication of both negative and positive results of prospective human studies is an obligation shared by physician-scientists, companies, and the peer-review community.³⁵

The physician-investigator obtains the consent from parents for their child to participate in the experiment. The young child, as a person who cannot provide informed consent, relies on the investigator and sponsor to ensure generalizability of results. Dissemination, in the form of peer-reviewed journal articles, helps to prevent other children from shouldering unnecessary risks in the future. With this research involving children who cannot speak for themselves, the obligation to publish is great. The need for publication is underscored by the funding mechanism for the trials. Although the immediate costs were supported with private sector funds, these trials were conducted with what amounts to public funding. The data from these trials resulted in the granting of an additional 6 months of sole market protection in the United States for approximately 90% of the products, and thus the public and public institutions paid for the higher-priced products during the 6-month delay in generic products coming to market. By law, pediatric exclusivity must be granted, irrespective of the outcome of the study, if the company conducts the trials requested by the FDA and the trials fairly respond to the written request. This policy was accepted because it was understood that negative data would often be just as important to physicians and parents as positive data from the clinical trials. Unfortunately, the fraction of studies published for which there was a key change in labeling was less than 50%; more discouraging is that only 26% of the studies in which the primary end point was safety were published.³⁶

In the context of previously conducted evaluations of research and subsequent publication, this cohort of studies has several unique attributes. Foremost is the development of the cohort. Much of the research that explores human experimentation and subsequent publication captures studies presented at meetings, or works backward from the peer-reviewed literature. This cohort, however, captures 100% of the studies undertaken because of an exceptional component of the pediatric exclusivity program: companies are required to submit all of the study's data to the FDA if they want to obtain the financial benefit of the extended sole market protection of their product line in the United States. A second unique attribute of these data resides within the purpose of the pediatric exclusivity program. The program provides a financial incentive to companies to obtain robust scientific data that will result in improved labeling of drugs given to children and subsequently improve pediatric health globally. This is hindered by the lack of publication in the peer-reviewed literature.

These data have several limitations and caution should be applied prior to interpreting the data in the context of any specific products, companies, research groups, or investigators. First, published articles may have been missed. We searched MEDLINE and EMBASE for publications; however, no strategy is perfect and we may have missed articles. These data do not include articles that have been submitted recently or are in press, however, companies were requested to submit all published, accepted, or in press articles based on studies conducted for pediatric exclusivity, a process that yielded no additional publications. The time between completion of the study and subsequent publication of multi-center collaborative research can be lengthy. Nevertheless, the results of at least 32 of the unpublished studies have been known for more than 5 years. The search efficacy of the authors resulted in over 5000 abstracts but several articles published prior to December 2005 may have been overlooked. Nevertheless, only 6 articles were found by only 1 author. A further limitation is that there is no control group for these data; it is possible that similar pediatric studies with negative results may suffer the same nonpublication fate as pediatric exclusivity trials.

The pediatric exclusivity program does not provide rewards or incentives for publication. Publication, and thus dissemination of knowledge, is a social benefit. Studies with negative outcomes can, and often do, contain important information for physicians and parents regarding the appropriate use of the product.

These data do not point solely at industry sponsorship as the root of the problem of lack of publication. In the current regulatory environment, there are few commercial rewards for publication. Pediatric exclusivity studies are typically completed late in the drug life cycle; there is little opportunity for the sponsor to use the information for promotional purposes. The economic benefits from pediatric exclusivity typically come from continued marketing protection of sales to adults. These studies are often done for drugs in which use in children is well established (eg, selective serotonin re-uptake inhibitors) or for drugs in which use in children is very limited (eg, drugs that improve bone density and reduce fracture risk for osteogenesis imperfecta). Promotion to pediatricians may therefore not be a marketing imperative. Having obtained additional marketing protection, sponsors may simply not see publication as a worthwhile investment of resources. Scientific journals have often been accused of reluctance to publish negative data, but this assertion has been challenged.³⁷

It is crucial to public health that currently available pediatric clinical trial data are made public and that future studies are published. Previous investigators have encouraged universal registration of clinical trials. Unfortunately, registration of trials, though increasing, is not adequate despite Food and Drug Administration Modernization Act legislation in 1997 that lead to the establishment of clinicaltrials.gov.^38- 39 Universal registration of trials is an important first step in achieving the goal of transparency of human subject experimentation, but is unlikely to ensure complete dissemination of results.

We found that 36 months following data submission to the FDA, publication of pediatric clinical trial data in a peer-reviewed journal is uncommon. A mechanism for data unpublished by 36 to 48 months following submission to the FDA could be peer-reviewed dissemination in a journal supplement. The focus of such results could be communication with the public, public health safety questions, and lessons learned in trial design and products within the same class. Peer-reviewed publication of all prospective trials involving children, including those conducted as part of the pediatric exclusivity program, is optimal.

Fully publishing pediatric data submitted for labeling will require a multifaceted solution that might also include legislative support. While the Best Pharmaceuticals for Children Act has been a substantive regulatory step forward, Congress might consider future legislation in which part of the incentive given for the completion of pediatric trials might be linked to peer-reviewed dissemination of results for those studies submitted early enough in their patent or marketing life cycle to permit such an activity.

The pediatric exclusivity provision has stimulated clinical trials and generated useful prescribing information for children more than any other regulatory or legislative process to date; however, the dissemination of these trial results in the peer-reviewed literature has been limited. Publication of studies conducted for pediatric exclusivity is an important step toward generalization of the knowledge obtained from the children enrolled in the trials and should be ensured for the benefit of pediatric public health.