Pediatr Drugs 2011; 13 (2): 119-124 1174-5878/11/0002-0119/$49.95/0

ORIGINAL RESEARCH ARTICLE

ª 2011 Adis Data Information BV. All rights reserved.

Limited Capacity in US Pediatric Drug Trials Qualitative Analysis of Expert Interviews Richard Wasserman,1,2 Alison Bocian,1 Donna Harris1 and Eric Slora1 1 Pediatric Research in Office Settings (PROS), Department of Research, American Academy of Pediatrics, Elk Grove Village, Illinois, USA 2 Department of Pediatrics, University of Vermont College of Medicine, Burlington, Vermont, USA

Abstract

Background: The recently renewed Best Pharmaceuticals for Children and Pediatric Research Equity Acts (BPCA/PREA) have continued industry incentives and opportunities for pediatric drug trials (PDTs). However, there is no current assessment of the capacity to perform PDTs. Objective: The aim of this study was to deepen understanding of the capacity for US PDTs by assessing PDT infrastructure, present barriers to PDTs, and potential approaches and solutions to identified issues. Design/Methods: Pediatric clinical research experts participated in semi-structured interviews on current US pediatric research capacity (February–July 2007). An initial informant list was developed using purposive sampling, and supplemented and refined to generate a group of respondents to explore emerging themes. Each phone interview included a physician researcher and two health researchers who took notes and recorded the calls. Health researchers produced detailed summaries, which were verified by the physician researcher and informants. We then undertook qualitative analysis of the summaries, employing multiple coding, with the two health researchers and the physician researcher independently coding each summary for themes and subthemes. Coding variations were resolved by physician researcher/health researcher discussion and consensus achieved on themes and subthemes. Results: The 33 informants’ primary or secondary roles included academia (n = 21), federal official (5), industry medical officer (8), pediatric research network leader (10), pediatric specialist leader (8), pediatric clinical pharmacologist (5), and practitioner/research site director (9). While most experts noted an increase in PDTs since the initial passage of BPCA/PREA, a dominant theme of insufficient US PDT capacity emerged. Subthemes included (i) lack of systems for finding, incentivizing, and/or maintaining trial sites; (ii) complexity/demands of conducting PDTs in clinical settings; (iii) inadequate numbers of qualified pediatric pharmacologists and clinician investigators trained in FDA Good Clinical Practice; and (iv) poor PDT protocol design resulting in operational and enrollment difficulties in the pediatric population. Suggested potential solutions for insufficient PDT capacity included (i) consensus-building among stakeholders to create PDT systems; (ii) initiatives to train more pediatric pharmacologists and educate clinicians in Good Clinical Practice; (iii) advocacy for PDT protocols designed by individuals sensitive to pediatric issues; and (iv) physician and public education on the importance of PDTs. Conclusions: Insufficient US PDT capacity may hinder the development of new drugs for children and limit studies on the safety and efficacy of drugs presently used to treat pediatric conditions. Further public policy initiatives may be needed to achieve the full promise of BPCA/PREA.

Background A critical pediatric issue over the past 40 years has been the approval and labeling of medications for use by pediatric patients. Over this period, it has been repeatedly estimated that 75–80% of pharmaceuticals possess insufficient labeling information to ensure adequate dosing, safety, or efficacy in

children.[1-6] Inadequate pediatric drug testing and the resulting inadequate labeling pose significant health risks for children. Without appropriate testing and labeling, the risk of being treated with doses that either are insufficient for therapeutic effect or toxic cannot be assessed. In 1997, the 105th Congress passed the Food and Drug Administration Modernization and Accountability Act (FDAMA).[7]

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This sweeping reorganization of the FDA included the pediatric provision. This provision, in section 111, provided economic incentives for the pharmaceutical industry to study drugs that are still on patent.[7] In 2002, the pediatric provisions in FDAMA were extended and augmented by legislation entitled Best Pharmaceuticals for Children Act (BPCA).[8] In 2003, the Pediatric Research Equity Act (PREA) was enacted to ensure that new molecular entities moving through the process for FDA approval had appropriate pediatric studies performed or planned prior to FDA approval.[9] This law represented a major philosophical and regulatory shift. For the first time, performance of pediatric studies prior to drug approval became the default policy, rather than an option or an afterthought. In September 2007, BPCA and PREA were renewed by the US Congress and signed into law. BPCA and PREA have increased industry incentives and opportunities for pediatric drug trials (PDTs). However, knowledge of the current capacity for PDTs is limited, as are the details of the challenges facing researchers, pediatricians in industry, government officials responsible for pediatric drug testing, and pediatricians who conduct trials in their clinical settings. Although an increased number of pediatric drug studies have been cited,[10,11] doubts have been raised about the number of publications resulting from these studies, the overall dissemination of the knowledge gained,[6] and the emphasis of the articles that have been published.[12] In addition, one research group has found that, at least through 2005, the number of published pediatric trials remains limited, especially when compared with the number of published adult trials.[13,14] In the context of conflicting evidence of the consequences of the legislative changes on PDT capacity, members of the American Academy of Pediatrics (AAP) Department of Research undertook to interview pediatric clinical research experts. The objective of the investigation was to deepen understanding of the capacity for US PDTs by assessing the adequacy of PDT infrastructure, barriers to present PDTs, and potential approaches and solutions to identified issues. The methods and results of this investigation are presented in this article. Methods From February–July 2007, we interviewed a group of research experts on the topic of US pediatric clinical research capacity. The sample of experts was chosen in the following manner. An initial informant list was developed through purposive sampling,[15] which was intended to maximize cognitive diversity (defined as ‘the extent to which the group reflects differences in knowledge, including beliefs, preferences, and ª 2011 Adis Data Information BV. All rights reserved.

perspectives’).[16] The diversity sought included informant sex, clinical specialty and subspecialty training, place of work, and present and past role(s) in PDTs (e.g. participant, protocol developer, regulator). The initial list was supplemented as interviews proceeded until a preliminary analysis of interviews indicated that no new information was emerging. A total of 33 pediatric clinical research experts ultimately agreed to participate in the semi-structured interviews. The script developed for the semi-structured interview included the following elements:  current and past employment;  experience with PDTs;  views of the existing pediatric pharmaceutical research infrastructure, including current capacity; challenges particular to pharmaceutical research; successes of the current system; impact of reauthorization/expiration of BPCA and PREA; relationship between federal agencies, industry, academia, and pediatric practitioners in PDTs; barriers to PDTs; opportunities for improvement; and queries regarding other information that we should consider. A physician researcher led each phone interview, while two health researchers took notes and recorded the calls. Interviews were conducted so as to cover all items in the script, but were varied to allow topics and responses that emerged from each informant to be pursued by the physician researcher. Health researchers created detailed written summaries of the interviews from the recordings and post-interview debriefing with the physician researcher. The informants verified the content of the summaries, correcting any inaccuracies. The health researcher/ physician researcher team then undertook qualitative analysis, employing established principles of qualitative research: grounded theory (deriving themes from interview content)[17] and multiple coding.[18] Coders employed ATLAS.ti (Scientific Software Development GmbH, Berlin, Germany) software to organize text data. The health researchers and the physician researcher independently coded each interview summary for dominant themes and subthemes. Physician researcher/health researcher discussion of theme and subtheme identification and coding variations resolved discrepancies, allowing a final consensus on themes and subthemes. The study was reviewed and approved, with respect to the protection of human subjects, by the Institutional Review Boards of the AAP and the University of Vermont, VT, USA. Informed consent was obtained from all interviewees. Results The primary and secondary roles of the 33 informants are categorized in table I. Pediatr Drugs 2011; 13 (2)

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Table I. Primary and secondary roles of the informantsa Role

No. of respondents (total n = 33)

Academia

21

Federal official

5

Industry medical officer

8

Pediatric research network leader

10

Pediatric specialist leader

8

Pediatric clinical pharmacologist

5

Practitioner/research site director

9

a The sum of categories = 66, representing both primary and secondary roles. Of note, many of the interviewees could have been categorized under more than two roles.

Dominant Theme

In the analysis of dominant themes and subthemes, a single dominant theme of insufficient PDT capacity emerged. Although most informants cited an increase in PDTs since initial passage of BPCA and PREA, the perceived capacity of the system was cited as insufficient to meet present and projected needs. Some of the many quotes expressing this theme are presented in this paragraph. A pharmacologist-academic remarked ‘‘By capacity, I’m interpreting that to mean reasonably trained pediatricians who are trained enough to participate, in a knowledgeable way, in a clinical trial. I think this is grossly, way, way below what it should be.’’ A pharmacologist-academic with experience as an industry medical officer said ‘‘What really is out there in terms of investigative capacity in the pediatric drug community y is limited y shrinking y often not very productive.’’ The head of a contract research organization conducting pediatric trials said ‘‘There are not enough sites, period.’’ Another pharmacologist-academic stated ‘‘I don’t think there is sufficient capacity at any level within the system at this point.’’ Subthemes on Insufficient Capacity

Four subthemes related to insufficient PDT capacity were identified. These subthemes were:  lack of systems for finding, incentivizing, and/or maintaining trial sites;  complexity/demands of conducting PDTs in settings that provide clinical care;  lack of pediatric pharmacologists and clinician investigators trained in FDA Good Clinical Practice (Good Clinical Practice is the international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects);[19] ª 2011 Adis Data Information BV. All rights reserved.

 poor drug trial protocol design resulting in operational and enrollment difficulties in the pediatric population. Representative quotes from the informants follow. With respect to the subtheme of lack of systems for finding, incentivizing, and maintaining trial sites, a pediatric pharmacologist working in industry commented ‘‘Some (in industry) y have tried to establish their own investigative site networks. The problem is that unless you’re focusing in one specific area repeatedly, where you’re likely to get these folks involved most of time, the networks tend to languish and sometimes go away as a resource.’’ That same individual observed ‘‘They (pediatricians) may be ready, willing and y even be good at doing clinical research, but if companies don’t know about them, they need to get in front of people and shop (offer for consideration) their own resources to them. That’s not an easy thing for a pediatrician to do out in a practice setting.’’ In addition, a pediatric subspecialist-academic-network leader said ‘‘Once the study is over, they (the trial sites) are gone and then you have to reinvent the wheel.’’ On the subtheme of complexity and demands of conducting PDTs in clinical settings, a pharmacologist-academic-network leader said ‘‘For most practicing pediatricians, the conflict between what needs to be done with respect to clinical research and every day clinical practice remains a significant barrier.’’ An academic subspecialist who has participated in many trials remarked ‘‘A lot of academics are shocked at the burden of doing an FDA study.’’ A pharmacologist-academic observed ‘‘The overhead for doing pediatric studies is higher than for adult studies.’’ Furthermore, a former practitioner and clinical research site director, now a government official, commented ‘‘New players are not used to having a medical monitor, data safety management boards, a clinical monitor y, i.e. a lot of people coming into the office to oversee the research implementation and data gathering.’’ With respect to the subtheme of lack of qualified pediatric pharmacologists and clinician investigators trained in FDA Good Clinical Practice, a pediatric pharmacologist-academic said ‘‘We are woefully inadequate with respect to trained persons at two levels: the general pediatrician and the pediatrician who has completed subspecialty training in clinical pharmacology.’’ A pediatric pharmacologist working in industry commented ‘‘My impression is that we don’t have nearly enough people y in the community who are engaged in Good Clinical Practice-level quality clinical research.’’ Also, the former practitioner/clinical research site director, who is now a government official, observed ‘‘There is (are) no next generation pediatric pharmacotherapists coming through the pipeline. Young pediatric pharmacologists are few and far between.’’ Pediatr Drugs 2011; 13 (2)

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On the subtheme of poorly designed PDT protocols that discourage pediatricians and children/parents from participating, a pediatric pharmacologist working for a contract research organization noted ‘‘Our challenge sometimes is educating or convincing the sponsor that their study design is not optimal for that population. We see a lot of bad protocols – some that are just inappropriate and not what I would want to do in the pediatric population.’’ A pediatric practitioner who conducts trials in his office noted ‘‘On the otitis front, y a couple of things have made it prohibitive – first they (FDA) require double-taps (pre- and post-treatment tympanocentesis) and second is to do placebo trials (for infants with otitis media).’’ Subthemes on Solutions for Insufficient Capacity

Four subthemes emerged related to potential solutions for the insufficient PDT capacity:  consensus-building among stakeholders to create PDT systems;  initiatives to train more pediatric pharmacologists and educate clinicians in Good Clinical Practice;  advocacy for high-quality PDT protocols designed by scientists sensitive to pediatric issues;  pediatric and public education on the importance of PDTs. On the solution subtheme of consensus-building among stakeholders to create PDT systems, an academic-pharmacologist who had worked in industry said ‘‘The overall arching goal is y getting the right people to talk together – the FDA, the pharmaceutical industry, and academia. If we can get those players to talk and share knowledge, cross-pollination will occur.’’ A subspecialist academic who had previously conducted many trials with industry suggested ‘‘What we need to do is find the place in the middle where we can collaborate together in the interest of the public health. That space, that place to meet, does not exist at this point.’’ For the solution subtheme of initiatives to train more pediatric pharmacologists and educate clinicians in Good Clinical Practice, a pediatrician working in industry, who had been an academic subspecialist said ‘‘for studies in kids, we want to make sure they are run by appropriately qualified people – pediatricians – and not ask that adult docs start running studies in kids. We need to train pediatricians. Where do you start doing that – with people already practicing pediatrics or by making residents and other trainees more aware and training them? I think its some combination of those two things.’’ And a government official who had been an academic subspecialist observed ‘‘We send people to courses to operate pieces of machinery, so why shouldn’t we send them to courses to participate in clinical research?’’ ª 2011 Adis Data Information BV. All rights reserved.

With respect to the solution subtheme of advocacy for highquality PDT protocols designed by scientists sensitive to pediatric issues, a pediatrician employed in industry, who had performed trials in his office when previously in practice, remarked ‘‘Companies with a really strong focus on pediatrics that have set their standards high for conducting pediatric research ought to be recognized and appreciated by the pediatric community y not chastised.’’ An academic pediatric pharmacologist observed ‘‘The formation of the Pediatric Office and Pediatric Advisory Committee at the FDA has been very helpful. But, while the pediatric leaders in the FDA y have all had the right goals and have said the right things, it has yet not filtered down to the review level, which is divided into independent therapeutic groups.’’ Midway through our interview process, in response to emerging barrier subthemes, we began asking our informants what the AAP might do to help remedy the situation of insufficient PDT capacity. For the solution subtheme of pediatric and public education on the importance of PDTs, an academic pediatric pharmacologist suggested ‘‘the unique role of the Academy is to make doing trials an attractive thing that would attract more pediatricians y who are not currently doing them or who are doing them but have no formal instruction in what they need to know to do them well.’’ A pediatrician working in industry – a former academic subspecialist opined ‘‘the AAP puts out nice informative pamphlets for parents on vaccines, etc. Have a pamphlet on clinical trials for parents – ‘What’s a placebo?’ ‘What does it mean to participate in a clinical study?’ Educate patients/families so they can make a more informed decision about whether they want to participate.’’ Discussion and Conclusions Our study’s limitations should be cited up front. Our focus was on the US and our informants were confined to US general pediatricians, pediatric subspecialists, and a single nonpediatrician (child psychiatrist). As such, their assessments may be of limited relevance to other countries. In addition, the relative lack of non-pediatrician informants may have limited the perspectives expressed. Finally, this is a qualitative analysis, and our conclusions must be tempered by the lack of quantitative confirmation. Analysis of our interviews nevertheless suggests that, despite the clear successes of recent incentives for PDTs provided by BPCA/PREA, there is insufficient US PDT capacity, which may hinder both generation of data for new drugs for pediatric patients and studies on the safety and efficacy of existing pediatric drugs. Our interviews also suggest that further initiatives, both in Pediatr Drugs 2011; 13 (2)

Pediatric Drug Trial Capacity

the public policy and private arenas, may be needed to achieve the full promise of the BPCA/PREA legislation. Aside from two references suggesting that PDT capacity is limited (see the Background section),[13,14] we were unable to find specific quantitative data to further corroborate our identified dominant theme of insufficient PDT capacity. For example, a literature review identified no analyses of data more recent than 2005 to quantify limited or incomplete accrual in pediatric studies, or evidence that a greater number of pediatric than adult studies are abandoned for inadequate subject accrual or that PDTs take significantly longer to accrue subjects than corresponding adult trials. We acknowledge that data of this sort may be hard to attain, since sponsors and contract research organizations do not readily share information about failed or incomplete drug trials, nor has the FDA made these data readily available in the past. Corroborating data to track PDT performance will be forthcoming in the future, however, as the reauthorization of BPCA and PREA requires the FDA to track the number and type of studies completed going forward from 2007.[20] Nevertheless, we remain confident that the unanimity of opinion about limited PDT capacity expressed by our informants lends strength to the validity of our findings at the time the interviews were conducted. Of the subthemes on barriers to sufficient capacity cited by our informants, several would require collaborative action among industry, pediatrician, and regulatory entities and/or complex policy solutions. For example, the lack of systems for finding, incentivizing, and maintaining trial sites is in part due to decades of neglect of PDT infrastructure, as industry rarely had financial incentives to develop and support networks of pediatricians to conduct such trials. Creating such systems would likely involve collaboration of industry and groups of primary care or specialist pediatricians, as well as an investment in education. Leadership for such an effort would be needed from multiple directions – from industry, government, academics, and the AAP. With respect to education, the shortage of qualified pediatric pharmacologists cannot be quickly remedied. This would likely require re-establishment of training grants funded by the government and/or industry. Increasing the number of clinician investigators trained in FDA Good Clinical Practice could be more quickly remedied. This would require creation of systems both to train pediatricians in this complex task and to market the concept of participating in PDTs to pediatricians who do not recognize the intellectual and financial value of this activity. The complexity and demands of conducting PDTs in clinical settings are not about to change since the amount of rigor and paperwork are dictated by federal statutes. Poorly designed ª 2011 Adis Data Information BV. All rights reserved.

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PDT protocols that discourage pediatricians and parents from participating, however, are amenable to improvement, albeit over time. For example, alterations in how the FDA finalizes its written requests, with more input from pediatricians within the agency, is already being accomplished, and increasing numbers of pediatricians working with and in the pharmaceutical industry could also help ameliorate this situation. The solutions to insufficient PDT capacity suggested by our informants will require careful thought, negotiation, and political, scientific, and academic will. Certainly, consensusbuilding among stakeholders to create PDT systems is within the realm of possibility. Initiatives to train more pediatric pharmacologists and educate clinicians in Good Clinical Practice can be created and sustained. Advocacy for highquality PDT protocols designed by scientists sensitive to pediatric issues is slowly taking shape. Finally, innovations in pediatric and public education on the importance of PDTs are beginning to appear.[21] As such, we may be cautiously optimistic about increasing capacity for PDTs. Acknowledgments Support for this study was provided by the AAP. The authors have no conflicts of interest to disclose. The authors thank the 33 individuals who agreed to be interviewed and share their thoughts for the study. The authors also thank Harry Pellman, MD, for serving as a subject in the pilot phase of interview development, and Richard Gorman, MD, for his thoughtful critique of an early draft of the manuscript.

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19. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH harmonised tripartite guideline: guideline for good clinical practice E6(R1) [online]. Available from URL: http://www.ich.org/LOB/media/MEDIA482.pdf [Accessed 2009 Sep 30] 20. American Academy of Pediatrics. Improvements made in the 2007 Reauthorization of the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) [online]. Available from URL: www.aap.org/advocacy/washing/therapeutics/docs/bpcapreaonepage.pdf2007 [Accessed 2010 Jun 19] 21. National Heart Lung and Blood Institute. No more hand-me-down research [online]. Available from URL: http://www.nhlbi.nih.gov/childrenandclinicalstudies/ index.php [Accessed 2010 Nov 29]

Correspondence: Dr Richard Wasserman, MD, MPH, University of Vermont College of Medicine, N310 Courtyard at Given, 89 Beaumont Avenue, Burlington, VT 05405, USA. E-mail: [email protected]

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