PEDIATRICS Vol. 108 No. 5 November 2001, pp. 1129-1134

Establishment of a Clinical Trials Office at a Children's Hospital

Mark J. Abzug, MD^*, and Elizabeth A. Esterl, RN^*

From ^* Children's Hospital and  Department of Pediatrics, University of Colorado School of Medicine, Denver, Colorado.

	ABSTRACT

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Objective.  To create a clinical trials office (CTO) at a children's hospital and assess its impact.

Methods.  Meetings with faculty and clinical trials groups were undertaken to develop a conceptual plan for an exclusively pediatric CTO designed to be a 1-stop office for sponsors, contract research organizations, and investigators. Guiding principles, eg, use of the CTO would be voluntary and paid for on a fee-for-service basis, were defined, and a business plan was developed.

Results.  The CTO opened in October 1997, offering a broad menu of services. Initial marketing efforts have been followed by steadily increasing use of the CTO, measured in a number of studies and investigators who use CTO services. Commensurate growth in CTO staffing has been required. Since the CTO's opening, the number of and revenues from industry-sponsored clinical trials performed at the hospital have been significantly greater than the pre-CTO baseline and have exceeded business plan projections. In addition, the proportion of industry-sponsored clinical research at the hospital that is administered by the CTO has expanded (now >50%). The increase in hospital revenues from industry-sponsored clinical trials has exceeded the cost of running the CTO. Studies performed by the CTO have involved a mix of general pediatric clinic/private office patients, subspecialty clinic patients, and hospitalized children.

Conclusion.  A CTO dedicated to pediatric clinical research can enhance the ability of a children's hospital to participate in the growing number of pediatric clinical trials.  Key words:  clinical research, clinical trials, drug studies, pediatric.

During the 1990s, while managed care was significantly changing the landscape of clinical care in the United States, parallel, important changes also were taking place in the clinical research arena. Clinical research previously had been based primarily in academic medical centers and for clinical trials of pharmaceuticals was often the product of a close, cooperative relationship between academic investigators and pharmaceutical sponsors. This relationship was altered with the development of private clinical/contract research organizations (CROs), which created a niche between the study sponsor and the investigator and became responsible for oversight of clinical trials. In addition, many clinical research studies were shifted from the academic center to private clinical research sites. Efficiency and cost-effectiveness in private settings (as compared with the reality and/or perception of the slow-moving bureaucracies of academic medical centers) were the driving forces behind this shift; these values replaced the value of working with "opinion leaders" and the prestige of performing studies in academic venues. This privatization of clinical trials research had a significant impact on the numbers of studies performed in academic settings: the market share of industry-sponsored clinical trials in medical schools dropped from 80% to 40%.¹

Several academic institutions responded to the pressure to enhance efficiency and productivity with the creation of clinical trials offices (CTOs). These centralized offices provided to institutional investigators personnel for and experience in performing clinical trials, obviating the need for each investigator to put in place his or her own team for each study. The CTOs provided pharmaceutical sponsors and CROs with a single, identifiable resource within complex medical institutions to place and conduct trials in a convenient, expeditious, and cost-effective manner, while still offering the traditional advantages of working with academic medical centers: investigators who are leaders in their fields, ample clinical sites and study participants, and the prestige of having studies performed in leading medical institutions. Experience showed that these CTOs were attractive to study sponsors. By 1999, 14 (11%) of 125 medical schools and affiliated teaching hospitals had established CTOs. The average annual growth in sponsored clinical trial income in academic sites with CTOs was 13% in 1995 and 19% in 1999, contrasting with an average annual growth rate of approximately 4% in medical schools that lacked centralized clinical trials organizations.^1,2 Although the number of academic institutions with CTOs has been increasing, we were unable to find in the medical literature (Medline database) descriptions of CTOs dedicated exclusively to pediatric clinical research.

As a result of the market forces described and the desire to facilitate faculty productivity in clinical research, the idea of establishing a centralized CTO at Children's Hospital of Denver, an affiliate of the University of Colorado School of Medicine, was formulated in the spring of 1996. This article describes the creation of Children's Hospital CTO and its impact to date.

	METHODS

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Development of the CTO Conceptual Plan

Small- and large-group presentations were made over several months to the pediatric faculty to introduce the CTO concept and solicit feedback. These presentations reviewed the changes in the nature of relationships between pharmaceutical manufacturers and academic researchers, the shift of clinical research from academic centers to private clinical research settings, and the effects of these trends on clinical research participation in academic medical centers. Experience with CTOs at other academic institutions was discussed, and comparisons of the growth in clinical research participation between institutions with and without such offices were made. Meetings also occurred with parties that had similar and potentially overlapping areas of activity, including the Pediatric General Clinical Research Center and adult clinical trials groups within the University of Colorado School of Medicine (which also were in their germinal stages) to identify helpful strategies, explore potential collaboration, and avoid duplication of services. For example, it was discussed that the Clinical Research Center would continue to serve primarily studies that benefit from an inpatient research unit and support research projects that have or are likely soon to have federal funding, whereas the CTO would provide assistance primarily for outpatient-based studies or for inpatient studies not localized to the research unit, and most CTO studies would be supported by pharmaceutical manufacturers. Another key early step was to learn about existent models via conversations and site visits with personnel at trials offices at other institutions.

From this process emerged a conceptual plan for a pediatric CTO. The CTO would be based at Children's Hospital, distinct from efforts to develop adult clinical trials groups within the University of Colorado School of Medicine. This decision was based on the geographic separation of Children's Hospital, where the vast majority of the University of Colorado pediatric clinical programs and pediatric clinical research resides, and the University of Colorado Hospital, which serves a primarily adult population; the separate grants administration already established at Children's Hospital; and the unique staff required to provide support for research in pediatric populations. The CTO's goals would be to facilitate existing research programs; recruit and implement new clinical studies and research programs; perform clinical trials both within Children's Hospital and with community pediatric practices; and be a 1-stop office for industry sponsors, CROs, and institutional investigators. CTO staff would assist investigators with regulatory documentation and budget negotiation, identification and recruitment of participants, performance of study procedures and follow-up, and completion of case record forms. Several guiding principles were identified early in the process as a result of feedback from our faculty and from learning what did (and did not) work effectively at other institutions. Studies would continue to be overseen by hospital investigators, who could hire CTO assistance. Use of the CTO's services would be voluntary, rather than mandated by the hospital or school of medicine. Those who would benefit from its services could use it, whereas investigators with their own, well-established clinical research teams would not be required to use the CTO's services. Use of the CTO would be paid for on a fee-for-service basis and would not involve any taxes of faculty resources.

Development of the CTO Business Plan

After this period of due diligence, the next phase involved development of a business plan. With the assistance of hospital finance personnel, a 5-year plan was developed. The plan started with the then-current baseline of pharmaceutical company-sponsored research at our institution and projected potential growth rates with a CTO assisting the research enterprise. Projected clinical research revenues were divided into those that would reimburse the CTO for its services, those that would be used for ancillary hospital services, and those that would go to the investigator for his or her efforts. Important is that it was recognized early that the major impact of a CTO would not (and should not) be for the CTO to be a "money maker." Rather, the impact of the CTO would best be measured by the number of clinical studies performed at Children's Hospital, the amount of total clinical research funds coming into the institution, and the support that these moneys provided to investigators' programs. The goal for the business plan was not for the CTO to be a profit center; rather, it was for the CTO to cover its own expenses while facilitating increases in research and research-associated funding for hospital investigators. The final business plan began with the assumption that the CTO would be responsible for an incremental rate of growth of 9% in clinical trials revenues (ie, 9% above the national average growth rate of 4% in institutions that lack centralized trials organizations), yielding a net 13% growth rate, which reflected the then-current average growth rate in trials revenues in institutions with centralized CTOs.² Beginning with this estimate, the business plan projected that the CTO would have a positive impact on overall institutional clinical research revenues (ie, the increase in clinical trials revenues would exceed the costs of running a CTO and other institutional expenses associated with performing clinical studies) by year 4.

Statistical Analysis

The institutional impact of the CTO was assessed by comparing the numbers of industry-sponsored clinical trials (and the amounts of associated direct income) performed at Children's Hospital before versus after creation of the CTO. In addition, for the time period after establishment of the CTO, comparison was made between the numbers (and amounts of associated direct income) of industry-sponsored clinical trials performed with the assistance of the CTO and industry-sponsored trials performed independent of the CTO. Statistical tests used were the Poisson model test, AR(1) time series model, and 2 sample t test.

	RESULTS

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Opening of the CTO

The conceptual and business plans for the CTO were presented in July 1997 to the hospital Board of Directors, which granted approval for initial funding of the CTO. The source of funds for this support was indirect cost recovery monies and proceeds from fundraising activities designated for hospital research programs.

Children's Hospital of Denver CTO officially opened its doors in October 1997 with the hiring of a study coordinator/nursing director, who directly reported to comedical directors, and with the assignment by the hospital of a physical office located in the hospital administrative office building. The role of the study coordinator/nursing director initially was to provide hands-on study coordination, with the expectation that as the CTO would grow, this individual would increasingly supervise the efforts of other nurse coordinators. Early CTO endeavors centered around marketing and public relations, with the creation of a brochure to advertise CTO services to local investigators and pharmaceutical sponsor contacts and a newsletter introducing CTO staff and describing ongoing trials to local investigators and referring physicians in the geographic region served by Children's Hospital.

The menu of services offered by the CTO is summarized in Table 1. Services can be requested on an "à la carte" basis, or the CTO can be requested to provide comprehensive assistance, in which the CTO performs most or all of these study functions. The CTO charges study budgets for the items selected from the menu of services; charges for these items vary for each study according to the complexity of and resources needed for that particular trial.

Growth of the CTO

At its inception, the CTO was requested to assist in the performance of 2 previously opened studies. Three months later, CTO assistance with new studies was requested for the first time, and after 6 months of operation, the CTO was assisting with 11 studies; for most of these, the CTO was providing comprehensive services, including study nursing. The number of studies that use CTO services has continued to grow steadily (Table 2). The CTO has provided comprehensive support for 72% of studies and comprehensive support excluding Institutional Review Board (IRB) submission for an additional 22%. For 6% of studies, limited CTO assistance was requested (IRB submission [2.5%], phlebotomy [2.5%], and participant recruitment [1%]). The number of investigators who use CTO services has continued to increase with time (Table 2).

A challenge for the CTO has been to manage responsibly the growth of its staff. The number of employees has been assessed frequently and adjusted to achieve a balance that would allow the CTO to accept new studies from investigators but not overextend CTO resources or result in underutilized personnel. This required periodic projections of numbers and intensity of studies, personnel needed to perform upcoming trials, and anticipated study revenues. During the first 2.5 years of operation, the most significant increase was in nursing positions, including the creation of the part-time role of regulatory administrator within 1 of the nursing positions (Table 3). In addition to the personnel hired by the CTO (and directly paid from study charges for CTO services), other personnel who are integrally involved in CTO functions but are not CTO employees include a research pharmacist, a hospital grants manager, and a hospital compliance/contracts officer. The research pharmacist's work with CTO studies comprises 33% of her activity and is reimbursed directly from study budgets.

Two significant events have had an impact on the growth and development of the CTO. The first is the designation in 1999 of Children's Hospital CTO and the Pediatric Trials Unit at the National Jewish Center for Immunology and Respiratory Medicine (both affiliates of the University of Colorado School of Medicine) as a joint site for the National Institutes of Health-sponsored Pediatric Pharmacology Research Unit (PPRU) network. The PPRU network was established to study cooperatively the pharmacology of drugs in children and to promote approval of pediatric indications for existing and new medications.³ This designation presented the challenge and opportunity of supporting an expanded base of clinical trials, including an increased number of phase I and II studies. The CTO administers PPRU network studies at Children's Hospital; the Pediatric Trials Unit administers PPRU studies at the National Jewish Center for Immunology and Respiratory Medicine. Since the creation of a PPRU site in Denver, 15 PPRU network studies have been performed at Children's Hospital, representing 18% of the 82 CTO studies performed to date (Table 2). The ultimate impact of participation in this network on the growth of the CTO remains to be determined.

The other major influence on the progress of the CTO was the suspension of the University of Colorado School of Medicine Multiple Institutional Review Board (COMIRB; the IRB that governs clinical research at Children's Hospital and other affiliates of the University of Colorado School of Medicine) for administrative concerns by the Food and Drug Administration (FDA) in September 1999. This move abruptly halted enrollment of participants into all clinical trials during September to December 1999. After approval was granted to COMIRB to reinitiate clinical research activities in December, all clinical trials were required, before beginning participant enrollment, to undergo rereview and reapproval; this process transpired between December 1999 and June 2000. The period of suspension and the subsequent delay in initiating studies until reapproval resulted in reduced enrollment at our site into 43 CTO-administered clinical trials (6 of which had terminated nationally by the end of the suspension period) and the withdrawal from our site by sponsors of 3 studies that had been planned to be performed by the CTO. The underenrollment in and withdrawal of CTO studies translated into an estimated institutional loss of $960 000 in study income (direct costs).

CTO personnel played several important roles in the recovery from this interruption in clinical trials activity. CTO nurses assumed temporary, part-time positions in the COMIRB office, assisting in the reorganization of that office's administrative procedures and, subsequently, aiding in administrative review and triage of the large number of applications submitted for IRB rereview. They also recorded the proceedings of the COMIRB meetings during the suspension and the 7-month protocol rereview periods. Finally, the CTO served the vital role for Children's Hospital's investigators of preparing resubmissions of 75 protocols (both CTO studies and non-CTO studies) according to the new, more extensive requirements for IRB submissions promulgated by COMIRB.

Institutional Impact

During the 3 years that preceded the CTO's creation (1995-1997), the number of industry-sponsored clinical studies at Children's Hospital was 20, 19, and 42 per year, respectively. Hospital investigators participated in 14 CTO studies and 36 non-CTO industry-sponsored trials in 1998 and, in 56 CTO studies and 46 non-CTO industry-sponsored trials in 1999. The sum of CTO studies plus non-CTO industry-sponsored trials per year for 1998 to 1999 was significantly higher than the number of industry-sponsored clinical studies per year in the period of 1995 to 1997 (P < .001, Poisson model test).

The CTO seems to have had a greater initial impact on clinical research revenues than that projected in the business plan. From 1993 to 1997, the annual direct income to Children's Hospital from industry-sponsored clinical trials was relatively stable, with a range of variability from 27% below to 38% above the mean for that period. In 1997, before full operation of the CTO, direct revenues from industry-sponsored studies decreased 29% compared with the preceding year. In 1998, after the opening of the CTO, there was a 56% jump in direct income to Children's Hospital from CTO studies plus non-CTO industry-sponsored clinical trials compared with the 1993 to 1997 mean and a 59% increase compared with 1997. Studies performed by the CTO during the calendar year accounted for 21% of the direct industry-sponsored clinical trials income and for 59% of the increase in industry-sponsored clinical trials revenues received by the hospital. In 1999, total direct revenues from CTO studies plus non-CTO industry-sponsored studies received by Children's Hospital were 134% higher than the 1993 to 1997 mean and 50% higher than the 1998 sum. The annualized growth rate compared with the 1993 to 1997 pre-CTO mean annual direct income from industry-sponsored clinical trials was 67%. Revenues from CTO-assisted studies accounted for 66% of the direct income to Children's Hospital from industry-sponsored studies. Whereas revenues from CTO-assisted studies in 1999 increased 367% compared with income from CTO studies in 1998, non-CTO industry-sponsored trials revenues decreased 34% during the same period. The revenues from CTO studies, taken alone, translate into a 27% annualized growth rate in direct revenues compared with the mean annual pre-CTO direct income to Children's Hospital from industry-sponsored research during 1993 to 1997. The annual direct revenue amounts from CTO studies plus non-CTO industry-sponsored clinical trials in 1998 to 1999 were significantly greater than the average annual direct income from industry-sponsored clinical trials in the pre-CTO period, 1993 to 1997 (P = .03 using AR(1) time series model and P = .02 using 2-sample t test). The increase in hospital industry-sponsored clinical trials revenues (above the pre-CTO baseline) in both 1998 and 1999 exceeded the costs of running the CTO (including salaries of the CTO nurses and part-time salaries of the co-medical directors) in both years. Moreover, the income paid to the CTO for services that it rendered (including, in 1999, core PPRU support provided for oversight of PPRU activities) covered 96% of the CTO's operating costs in 1998 and 104% in 1999.

Of the total revenues (direct + indirect) received from CTO studies to date, 26% has been paid to institutional investigators and 40% to the CTO. The remainder has been divided among the hospital (including indirect cost payments), hospital ancillary services (eg, laboratory, pharmacy, radiology), participant reimbursements, and miscellaneous charges.

Current Status

By the middle of 2000, there were 53 ongoing CTO studies; 29 other CTO studies had been completed. The vast majority of study sponsors were pharmaceutical manufacturers, although several studies sponsored by the Centers for Disease Control and Prevention and the National Institutes of Health also used CTO services. Twenty-seven investigators from 17 divisions in the hospital had used CTO services since its creation, representing 16% of faculty in the Department of Pediatrics (primary or secondary appointments) based at Children's Hospital. Seventeen of the 82 studies (21%) performed by the CTO during this period involved outpatient populations of well children or children who presented with common, nonsevere illnesses. These studies were conducted at both the hospital-based general pediatric clinic (n = 17) and private pediatric offices (n = 8) and primarily involved evaluation of vaccines or of therapies for viral upper respiratory tract infection or otitis media. The remainder of studies involved subspecialty clinic patients and/or hospitalized children.

	DISCUSSION

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The numbers of clinical trials administered by the CTO and of investigators who use CTO services increased steadily during the first 2 years of its operation. During this period, the growth in the number of sponsored clinical studies at our hospital and in institutional clinical trials revenues has far exceeded the growth rate projected in the CTO business plan, and the CTO has assumed an expanding role in institutional industry-sponsored research (although CTO services have not been limited to pharmaceutical-sponsored research). The creation of a CTO has not merely shifted industry-sponsored research from individual investigators' research teams to a centralized research operation; rather, the establishment of a CTO has contributed to real growth in research activities. The increase in numbers of studies, investigators who use CTO resources, and study revenues all underscore the value of a centralized trials office.

Several factors likely contributed to the initial successes of the CTO. The underlying principles chosen for the CTO have engendered institutional acceptance. No faculty taxes are used to support the CTO, and increased clinical trials revenues generated by the existence of the CTO are intended primarily to benefit the institution and its investigators rather than the CTO itself. In addition, use of the CTO is voluntary, so there is no perceived threat to existing research teams. Because reimbursement for CTO services is paid from study budgets on a fee-for-service basis, with the principal investigator retaining the portion of revenues for his or her study functions, the CTO has been an attractive resource for our investigators, particularly those who lack study teams of their own. Operationally, several factors have helped the CTO perform well. These include the hiring of a nursing director who is experienced in clinical research and maintenance of a nursing staff that is trained in clinical research; synergistic interaction with related hospital research personnel (grants manager, research pharmacist, compliance/contracts officer); controlled growth of the CTO staff proportional to need; and performance of studies directed at a breadth of pediatric populations, from ambulatory, well children to critically ill, hospitalized patients, and involving general pediatric practitioners and a wide variety of pediatric subspecialists.

External forces that favor a pediatric CTO include the increasing desire for efficiency on the part of pharmaceutical industry sponsors and CROs and the increasing number of clinical trials that are being performed with children. The latter is the result of a major attitudinal shift that occurred in the 1990s with respect to the study of medications in children. Increasing concern was expressed during this period about off-label use of medications in children, especially use of drugs in very young children for whom adequate study had not been performed.^4,5 Whereas clinical trials of new drugs previously had been considered a threat to the rights of children, the prevailing political opinion changed to one in which not studying important agents in children was neglecting the best long-term interests of the pediatric population. This change was codified in the 1997 Food and Drug Administration Modernization Act, which provided for additional market exclusivity if pharmaceutical companies conducted requested studies in children, and a 1998 FDA ruling requiring that manufacturers provide adequate data to support pediatric use for certain new and marketed drugs.⁶ As expected, these provisions have generated more pediatric clinical trials. A total of 184 pediatric drug study proposals were filed with the FDA in 1999 to 2000, contrasting with the 70 filed between 1991 and 1997.⁷ This trend is reflected in the increased number of industry-supported studies in which our investigators participated in 1997, even before the creation of the CTO, and likely contributed to the increases in industry-sponsored clinical trials income that we observed in 1998 and 1999. Establishment of the CTO, therefore, is not the sole factor responsible for the growth in clinical trials activities at our hospital. However, its presence has facilitated our participation in the enlarging sphere of pediatric pharmaceutical research, thus enhancing our institution's ability to meet the needs of the FDA mandate to increase study of medications in children. The presence of a highly visible CTO serves to attract inquiries for study participation from industry sponsors, particularly after successful completion by the CTO of previous studies from the same sponsors.

This expansion in pediatric clinical trials, particularly in industry-sponsored studies, presents a variety of challenges, many of which have been emphasized in the lay and professional press.^8-16 Paramount among these are issues related to conflicts of interest. Investigators and their institutions may be influenced to increase participation in and enrollment into trials because of direct financial gains (eg, if they are stakeholders in pharmaceutical industry sponsors) or because compensation for participant enrollment into clinical trials is needed to support investigators' salaries or institutional coffers. This pressure can lead to enrollment practices that are coercive or that involve less than full disclosure, threatening the responsibility of physician-investigators to protect the safety of human subjects. This risk is especially significant when dealing with vulnerable populations such as children. Financial considerations associated with participation in clinical trials can, in subtle or obvious ways, bias the integrity of study design, oversight, and reporting of results. Finally, financial pressures may lead physicians to participate in industry-sponsored research that does not appreciably advance science or health care and may distract from endeavors with more academic and scientific worth.

It is hoped that establishing CTOs in children's hospitals will help address these issues. By attracting industry-sponsored pediatric research to academic centers, CTOs should facilitate scientific and ethical oversight of this research. CTOs can (and should) establish standards for their research staff to include adequate training in performance of clinical research with children, including relevant ethical and regulatory considerations. The presence of highly trained CTO staff will foster adherence to the growing requirements for documentation and regulatory compliance associated with clinical research and hopefully serve as a safeguard against any tendencies toward improper recruitment and enrollment strategies by investigators. In prioritizing its resources, academic pediatric CTOs should emphasize performance of clinical studies that hold promise for important scientific discovery; promote development of novel therapies for pediatric diseases; and/or provide needed safety, efficacy, and/or dosing information to foster optimal use of pharmaceuticals in children.

Competitive forces provide incentive for academic centers to perform clinical trials efficiently. As attitudinal and regulatory changes increase the number of pharmaceutical studies designed for children, there exists additional motivation to perform pediatric clinical trials efficiently in both ambulatory and inpatient settings. Our preliminary experience suggests that creation of a pediatric CTO is an effective means of meeting this first challenge. The larger vision for a CTO at a children's hospital will be fulfilled if the CTO facilitates meaningful research that yields improved care for children while safeguarding the rights of pediatric patients and promoting scientific integrity.

	ACKNOWLEDGMENTS

We acknowledge the vision and contributions of Harley Rotbart, MD; the support of M. Douglas Jones, MD, Paul Fennessey, PhD, Dori Biester, RN, PhD, and Demosthenes Argys; and the dedication of Susan Brantz, Jennifer Carroll, Lori Claussen, Sara Gerrie, Caren Holland, Monique Hulleman, Melanie Nelson, and Carrie Vonderheide. RaeAnn Paden helped track study revenues, Mary Jo Yantis assisted with the business plan, and Todd Mackenzie, PhD, provided statistical support.

	FOOTNOTES

Received for publication Dec 13 2000; accepted May 4, 2001.

Reprint requests to (M.J.A.) Children's Hospital, Box B055, 1056 E 19th Ave, Denver, CO 80218. E-mail: abzug.mark{at}tchden.org

	ABBREVIATIONS

CRO, clinical/contract research organization; CTO, clinical trials office; IRB, Institutional Review Board; PPRU, Pediatric Pharmacology Research Unit; COMIRB, University of Colorado School of Medicine Multiple Institutional Review Board; FDA, Food and Drug Administration.

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