Portal de Periódicos da CAPES

Pediatric Clinical Trials: Shall We Take a Lead?

2002; Lippincott Williams & Wilkins; Volume: 94; Issue: 1 Linguagem: Inglês

10.1097/00000539-200201000-00001

1526-7598

William J. Greeley,

Health Systems, Economic Evaluations, Quality of Life

In this issue of Anesthesia & Analgesia appears the report of a clinical trial of oral midazolam (1). Why does this report of an industry-sponsored clinical trial deserve our attention? After all, there have been numerous previous studies on the same topic. This study was used, in part, as evidence for Food and Drug Administration (FDA) approval of this formulation of midazolam in children. As such, this multi-centered trial represents the vanguard of a new era in which children will have access to therapies that have proven safe and effective. After 107 deaths from elixir of sulfanilamide, Congress enacted the Food, Drug and Cosmetics Act of 1938 (2). Subsequently, the 1962 Harris-Kefauver Amendments were enacted in the aftermath of birth defects produced by thalidomide and deaths from gray baby syndrome attributable to chloramphenicol. As a result of these laws, pharmaceutical companies have been required to conduct well-controlled clinical trials to demonstrate that new drugs and biologics are both safe and effective. Unfortunately, children have not been major beneficiaries of these legislated protections. Drugs that are widely used for children, such as oral antibiotics, antihistamines, asthma medications, and vaccines, have been frequently studied and labeled appropriately, although not always for all age groups. However, drugs targeted at many important but less common pediatric diseases typically have not been studied or labeled other than to carry a disclaimer stating that “Safety and effectiveness in pediatric patients have not been established”(3). By 1973, 78% of the drugs approved for use in the United States had no indication for children, no dosage information for children, and no exclusion for children below some age range (4). The FDA promulgated additional requirements for pediatric labeling in 1979 but without any effect on the percentage of drugs labeled for children (5). As a result, the FDA issued a new rule that made it easier to obtain labeling for pediatric indications (6). The 1994 rule permitted extrapolation of adult efficacy and safety data to pediatric age groups when the course of the disease in adulthood and in childhood was the same. When applicable, trials to establish age-related pharmacokinetics (PK) and safety data in children might suffice to extend to labeling. When the relationship between dose or blood level and response was uncertain, pharmacodynamic (PD) data would be needed too. The need for PK/PD data in children to determine correct dosage is well founded. A number of factors, including age, sex, underlying disease (especially those affecting renal or hepatic function), and concomitant therapies, may affect a drug’s kinetics or dose response. Moreover, the changes in body composition and metabolism that occur with growth and development may preclude direct translation of adult dosage guidelines to pediatric patients (4). Unfortunately, the 1994 rule was voluntary and failed to increase the number of pediatric clinical trials, the percentage of new drug applications (NDAs) that contained labeling for children or the percentage of postapproval commitments to conduct pediatric trials successfully completed (7). Recently, a two-pronged approach to solving what has seemed an insolvable problem has been underway. First, Congress passed the Food and Drug Administration Modernization Act of 1997 (FDAMA), which provides incentives in the form of a 6-mo extension of patent or marketing exclusivity for conducting pediatric clinical trials for already approved drugs that meet the requirements of a written request (8). The second, more permanent, component of the pediatric drug labeling solution involves the 1998 final rule that mandates that sponsors obtain data in pediatric patients before submitting a NDA. This rule applies not only to new molecular entities but also supplemental NDAs submitted after December 2, 2000 (7). So far, FDAMA has had a dramatic effect on the number of clinical drug trials in children (9). As of August 6, 2001, the FDA had received 245 proposed pediatric study requests and had issued 197 written requests. On average, slightly more than two clinical trials have been required per written request, meaning that more than 400 clinical trials involving children have been completed, are underway or are in planning. As of August 2001, 35 active moieties have been granted extension of exclusivity under the provisions of FDAMA, including midazolam, sevoflurane, tramadol, propofol, and remifentanil. FDAMA has demonstrated the feasibility of conducting pediatric clinical trials making it hard for sponsors to use lack of feasibility as an excuse for not conducting pediatric trials in the future. Age-appropriate formulation remains a major obstacle for developing therapeutics for children. Most anesthetics are inhaled or administered IV, but most drugs for children, including outpatient analgesics and preoperative sedatives, are best administered orally. Pediatric patients frequently receive extemporaneous preparations without known bioavailability or efficacy. Coté et al. (1) highlight the inadequacy of this approach. Prior studies suggested that 0.5 mg/kg was the minimum effective dose of oral midazolam and therefore the investigators used one-half this dose to serve as an active control group. Unfortunately for the trial, the 0.25 mg/kg dose of midazolam was effective for most children. The efficacy of this smaller dose of midazolam was probably because of the use of a standardized preparation with known bioavailability. Generalizations from reports of clinical trials that use extemporaneous drug formulation should be viewed with increased skepticism because the validity of the results hinges not just on the study design, execution, and analysis but also on the ability to replicate the formulation. It would seem that some portion of the substantial profits made by obtaining patent extension should be reinvested in developing commercially available oral liquid products that would provide vastly increased benefits to children compared with continued use of extemporaneous formulations. Although FDAMA sunsets at the end of 2001, it appears that Congress might extend the incentives in some modified form, including capping the profits by placing limits on the duration of exclusivity extension for blockbuster products. With the exception of ibuprofen, FDAMA has failed to stimulate the study of generic drugs. Congress is also exploring mechanisms to fund studies of generics to overcome this gap. Pediatric investigators should begin considering which common generic drugs deserve study in preparation for potential federal funding for clinical trials. Not all of the blame for the lack of labeling information for drugs falls on the shoulders of the pharmaceutical industry. Academic medicine and pediatric practitioners need to do more as well. Drug development must become an acceptable and rewarded pursuit for academic investigators. Department chairmen, committees on appointments and promotions, and peers need to recognize the value in this work. Study design, data management and interpretation, and information dissemination are important components of the trial process. Without incentives (e.g., time, space, resources) and rewards (e.g., recognition and promotion) academic physicians will not participate as investigators. To facilitate academic involvement, sponsors need to be sensitive to the needs of investigators and foster collaborative research that intellectually engages participants. Investigators must have the right to examine the data independently and submit manuscripts for publication, even if the results are negative. This is important for medical practice because such publications influence the manner in which physicians treat patients. Because authorship is the currency by which academicians gain recognition and ultimately promotion, changes are needed to appropriately credit and acknowledge all participants. Drummond Rennie and others have proposed replacing authorship with a new paradigm. Instead of authors, they propose that all contributors would be listed in a manner akin to film credits (10,11). Listing the specific contributions (e.g., concept, protocol development, planning, statistical analysis, interpretation, patient enrollment, drafting the article, critical revision) of all trial participants will add clarity and accountability (12,13). The number of authors listed on the byline of an article is limited, but acknowledgments can recognize all that make important contributions. Failure to communicate the extent of each contributor’s participation ultimately devalues the listing of the publication on the investigator’s curriculum vitae while the practice of limiting the number of authors discourages many from participating at all. Clinical trials also require resources that few individual investigators possess, including nonclinical time, trained research coordinators, rapid processing by institutional review boards, and streamlined research contracting. The failure of institutions to provide the necessary resources may diminish the number of available research sites and impede enrollment into trials. The evidence suggests that institutions that have developed a central trial office structure to oversee and support clinical trials have witnessed much greater growth in the number of industry-sponsored trials than institutions that continue to leave this up to individuals and departments. The scarcity of well-controlled clinical trials has forced pediatric specialists to try new and understudied drugs to treat childhood medical conditions. In the past, each patient represented a nonrandomized, uncontrolled experiment. FDAMA has provided powerful financial incentives to the pharmaceutical industry, and the 1998 rule will hopefully provide the regulatory clout to require manufacturers to obtain useful data for children. Justice demands that everyone in society reap the benefits of the research enterprise. In return, investigators, parents, and children must be willing to participate in well-designed clinical trials that generate generalizable data that can benefit future patients. The framework is now in place; we must all do our part to make it a reality. As physicians, we are the individuals responsible for the prescribing of drugs to patients. Shall we take a lead in demanding appropriate clinical trials in children, or continue to prescribe without evidence?