The Need for Pediatric Drug Development

Therapeutic tragedies in pediatric patients contributed to formulation of the legal requirement that new medications had to be carefully studied before they could be approved for interstate sale.(1) Despite this, the majority of pediatric patients who require treatment are prescribed medications which are either not approved for pediatric use or contain incomplete directions for pediatric use in the approved product label.(2, 3)

Sulfanilamide Elixir Exposes the Risk of Limited Medication Regulations

In 1938, development of a liquid formulation of sulfanilamide, an antibiotic effective against streptococcus, staphylococcus, syphilis, and gonorrhea, allowed oral dosing of pediatric patients who could not swallow the sulfanilamide tablets.(4) Unfortunately, the solvent used to dissolve sulfanilamide was sweet tasting, raspberry flavored diethylene glycol, an industrial solvent that was not then recognized as a toxin. Reports of nausea, vomiting, renal failure, and hepatic dysfunction, with a 30% mortality rate followed the geography of the salesmen’s routes through Oklahoma, Louisiana and New York. Despite more than 100 deaths, there were no existing laws restricting manufacture of this formulation, Massengil Elixir of Sulfanilamide, except that the term elixir was reserved for ethanolic solutions.(4) Mr. Samuel Massengil was fined $26,100 for selling a misbranded medication. The chemist who developed the solution committed suicide. In 1938, this tragedy led to passage of the Food, Drug and Cosmetic Act (FDCA) that required approval of all new drugs through a New Drug Application (NDA), disclosure of all active ingredients, and evidence that the drug was safe when used according to the directions on the label. Proof of efficacy was not required, so broad therapeutic claims could be advertised. The Agency was given only limited regulatory powers, and medications could be marketed if no objection was raised within 60 days of the New Drug Application.

Thalidomide, Nearly a US Disaster

Thalidomide was once considered a popular sleep aid and treatment for nausea during pregnancy. It was marketed over the counter in Germany in the 1950’s, until it was associated with neuritis, and then a prescription was required in 1961.(5, 6) Thalidomide was widely marketed in Europe by many names.

In 1961, a dramatic increase in a rare, disfiguring, congenital anomaly, phocomelia, was discussed at medical conferences in Europe. Thalidomide during early pregnancy was the suspected cause of this multiple malformation syndrome that included severe shortening of the extremities, malformations of ears, heart, intestines, and other structures, depending on the embryologic stage at the time of exposure.(7, 8) Thalidomide was being evaluated for approval in the U.S. at that time with over 2,500,000 doses distributed in the U.S. Dr. Frances Kelsey delayed FDA approval initially because of the polyneuritis and neuropathy observed in England and Germany, but later because she had heard of the association of phocomelia with thalidomide.(5)

Kefauver-Harris Amendment to the FDCA Changes FDA’s Ro le in D rug Ov ersight

Congressional hearings begun by Kefauver and Harris in 1959 were focused on the high price of medications. With the identification of thalidomide induced severe congenital anomalies, they changed direction and extended the powers of the FDA. For the first time, the FDA was given a major regulatory role in protecting U.S. citizens from ineffective medications. New provisions included a requirement for Good Manufacturing Practice, requirement for filing an application with the FDA before starting testing (Investigational New Drug application), and the authority to remove marketing approval if new evidence showed a lack of safety or effectiveness. Congress required that new drugs must be demonstrated to be not only safe, but also effective based on well-controlled, scientific clinical trials before they could be marketed. Pediatric tragedies served as the genesis of this Congressional requirement, yet the actions and efforts that followed were focused primarily on drug development for adults.

These new FDA laws had an unanticipated chilling effect on studies of drugs in children. Some argued it was totally unethical for children to participate in clinical studies and become the human equivalent of a test animal. Others were concerned about the costs and difficulties of conducting studies in children who could not consent for themselves. As new drugs were approved, pediatric patients were seldom included in clinical trials. Without children’s participation in clinical trials, no pediatric prescribing information was generated for inclusion in the label for the new medication. Instead, pediatric prescribing often occurred with nothing more than anecdotal experience. Prescribers had no formal guidance in the use of medications for pediatric patients and had to rely on the familiar text in many approved labels, “safety and effectiveness of [add a drug name] have not been established in pediatric patients.”

Importance of a Drug Label

The emphasis this paper places on labeling of drugs for children reflects the high data-driven bar required to achieve labeling by the FDA. The study design must undergo review by the local IRB as well as the FDA for scientific validity and ethical appropriateness. The study must conform to the present federal guidelines for Good Clinical Practice. Finally, all the data undergo careful scrutiny by monitors to confirm the data’s accuracy before review both by the sponsor and by the FDA. Thus, the information contained in a final approved product label implies that the data supporting that information and/or a given claim meets rigorous scientific, regulatory, and clinical standards. The dearth of approved pediatric product labeling for medications used routinely to treat children reflects a failure to meet these standards.

Pediatric Patients, Therapeutic Orphans

Just 5 years after the FDCA amendments to require demonstration of safety and efficacy for approval of new drugs, Dr Harry Shirkey described children as “Therapeutic Orphans,” because the 1962 legislation allowed their exclusion from testing of new drugs.(9) Wilson provided objective measures of how few drugs were labeled for pediatric patients in 1975 based on a review of the 1973 Physician’s Desk Reference (PDR) where he found that 78% of drugs lacked adequate pediatric labeling.(10) Part of the problem, according to Wilson, was the paucity of people trained in pediatric clinical pharmacology.(11) Of the first 231 people certified by the American Board of Clinical Pharmacology, only 19 (8%) expressed an interest in pediatrics. Thus, the cadre of highly trained, specialized professionals capable of both championing and actively contributing to pediatric drug development was insufficient to adequately impact this problem.

First Guidelines for the Evaluation of Drugs in Infants and Children

The discipline of pediatric clinical pharmacology was emerging and defined itself based on characterization of the impact of maturation, growth and development on drug disposition and action. This effort was led in the US by Drs. Sumner Yaffe, Bernard Mirkin, Ralph Kauffman, Sanford Cohen, Lester Soyka, Jacob Aranda, John Wilson, and several others who worked to increase pediatric studies of drugs. In December, 1970, the Drug Research Board of the National Research Council of the National Academy of Sciences evaluated the status of Clinical Pharmacology and acknowledged the lack of studies to support pediatric therapeutics and of pediatric experts to conduct clinical trials.(12) They stated, “If the abyss of ignorance surrounding pediatric therapy and the introduction of new drugs into children is to give way to a scientific approach, it will be necessary to develop a national program with this as a clear goal and with appropriate support mechanism.” They concluded “The need for clinical pharmacologists within the specialty of pediatrics is particularly great. The development of pediatric pharmacology requires special attention.” This need remained unmet until 1994 when the Pediatric Pharmacology Research Units (PPRU) were established and funded by NICHD.

Several years before the PPRUs were established, the AAP began efforts to support studies of drugs in children and to counter the claims that participation of children in clinical trials was unethical. The AAP Committee on Drugs (COD) started detailed discussion of how to conduct pediatric studies. They authored a report for the FDA in 1974, “GENERAL GUIDELINES FOR THE EVALUATION OF DRUGS TO BE APPROVED FOR USE DURING PREGNANCY AND FOR TREATMENT OF INFANTS AND CHILDREN”. This comprehensive document was not published or endorsed by the FDA, but is available from the AAP archives.(13) It would be decades until the FDA produced their first guidance document describing drug development for pediatric patients, although it did not address the needs of the neonate.(14)

Later AAP Guidelines for the Ethical Study of Drugs in Pediatric Patients

A few years after the report for the FDA, the COD published the first edition of “Guidelines for the Ethical Study of Drugs in Pediatric Patients.”(15) This comprehensive review of how and why pediatric patients should participate in pharmacologic studies was published two years before the historic Belmont Report(16) that contained many of the same principles. Both documents carefully distinguish between experimentation, “the use of unproven methods, medications, or doses” and research, “the well-controlled, systematic investigation intended to develop new and useful knowledge”. The concepts in this COD statement undergo regular updating and remain relevant today, “The Committee believes that it is unethical to adhere to a system which forces physicians to use therapeutic agents in an uncontrolled experimental situation virtually every time they prescribe for children. Furthermore, it is not only ethical but also imperative that new drugs to be used in children be studied in children under controlled circumstances so the benefits of therapeutic advances will become available to all who may need them.” (17, 18) Unfortunately, these documents did not immediately stimulate much clinical research in children. They did, however, catalyze the thinking and actions of a growing group of individuals in the U.S. who came together to advance innovative legislation designed to advantage children in the drug development process.

Institute of Medicine Workshop, a Turning Point

A critical juncture in efforts to increase research and labeling of drugs for children came in April of 1990 with the convening of a two day workshop on Drug Development and Pediatric Populations sponsored by the Forum on Drug Development of the Institute of Medicine co-sponsored by NICHD and AAP.(19) Representatives from the FDA, NIH, pharmaceutical industry, and academic pediatrics identified solutions to barriers to drug development for children. Recommendations from the Workshop included: 1) that the FDA explore innovative ways to encourage and accommodate labeling of drugs for children; 2) that the NIH provide essential funding for pediatric pharmacology research and training of researchers with expertise in pediatric pharmacology; 3) that Congress develop and pass legislation to mitigate the disincentives to drug development for children; and 4) that the pharmaceutical industry develop the infrastructure and expertise within the industry to conduct pediatric trials that would support pediatric labeling. The implementation of these recommendations accelerated advancements in pediatric drug research.

1994 Final Rule

An important stimulus and assistance to FDA labeling of drugs for pediatrics was established in 1994.(20) The 1994 Final Rule, “is intended to provide practitioners with more pediatric use information in the labeling of human prescription drug products so that practitioners will have more reliable information upon which to base a decision to prescribe a drug for use in their pediatric patients.” “FDA may approve a drug for pediatric use based on adequate and well-controlled studies in adults, with other information supporting pediatric use. In such cases, the agency will have concluded that the course of the disease and the effects of the drug, both beneficial and adverse, are sufficiently similar in the pediatric and adult populations to permit extrapolation from the adult efficacy data to pediatric patients. The additional information supporting pediatric use must ordinarily include data on the pharmacokinetics of the drug in the pediatric population for determination of appropriate dosage.” Sponsors were also required to reexamine existing data to determine whether the “Pediatric Use” subsection of the labeling could be modified based on data in their possession or published studies that were adequate and well-controlled.

Although this rule sounded helpful, it had little immediate impact on pediatric labeling. Few academic studies met the standards needed for FDA labeling, and few companies had pediatric data in their files. The 1994 Final Rule did introduce the concept of extrapolation to facilitate pediatric labeling which was clarified in subsequent legislation(21) and discussed in a publication by the FDA pediatric staff.(22)

FDA Modernization Act of 1997, A Successful Experiment

The first truly impactful legislation to increase studies of medications for the pediatric patient was the FDA Modernization Act of 1997 (FDAMA).(23) This law used a capitalist approach of rewarding companies for pediatric studies of new drugs that had not yet received final FDA approval. In return for the voluntary completion of studies specified by the FDA in a Written Request (WR), the sponsor of the drug would receive a six-month extension of market exclusivity resulting in protection from a competitor marketing a product with the same active ingredient. Market protection applied to all products that contained the active moiety and essentially extended the market life of the product. The WR could specify studies of off-label indications if those were judged to be important for pediatric therapeutics. A detailed study of the economic return from qualifying for exclusivity refuted the contention that this legislation was a financial windfall for industry.(24) Some studies actually lost money for the companies with returns ranging from -$8.9 Million to $507.9 Million. Even for the drugs with large sales, the return was not as large as predicted.

Pediatric Research Equity Act, 2003

The year after implementing the voluntary FDAMA program, sometimes referred to as the “carrot”, it was complemented with the “stick”, a requirement for study of new drugs in the pediatric population, the 1998 Final Rule.(25) This regulation required pediatric study of new drugs that might provide a therapeutic benefit to pediatric subjects and that might be used in a substantial number of pediatric patients. The indications that could be tested in children were limited to those for which approval was being sought, which often were not studies pertinent to the clinical needs of children. This Rule was implemented by the FDA and struck down by Judge Henry Kennedy, Jr in 2002 noting, “The pediatric rule may well be a better policy tool than the one enacted by Congress. It might reflect the most thoughtful, reasoned, balanced solution to a vexing public health problem. The issue here is not the rule’s wisdom. The issue is the rule’s statutory authority, and it is this that the court finds lacking.”(26) Fortunately, congressional legislation was already in preparation and rapidly incorporated into law virtually all the provisions of the 1998 Final Rule as the Pediatric Research Equity Act (PREA) of 2003.(27) This requirement for studies complemented the next iteration of FDAMA, titled the Best Pharmaceuticals for Children Act (BPCA), which passed in 2002 and preserved the voluntary incentive program to extend market exclusivity.(28) These two laws have complemented each other to significantly increase the study of drugs and labeling for pediatric patients. Both the BPCA incentive program and the PREA requirement program were made permanent in 2012, but this did not apply to all the provisions in these laws. The provision of BPCA that authorizes the NIH research program to study and label older drugs was not made permanent in 2012.

Challenge of Pediatric Labeling of Off-Patent Drugs: The NIH-related BPCA Process

Pediatric clinical trials of medications were increasing, but many of the drugs used every day in pediatric practice were older drugs without sufficient pediatric labeling or residual patent protection that could qualify for pediatric market exclusivity. Options to incentivize study of these generic, older medications were limited. To increase such studies, the 2002 BPCA law in section 4091 also created a foundation at the NIH to fund studies of off-patent drugs that could potentially be labeled for pediatric treatment. Donations were requested from PhRMA companies that had received market exclusivity through FDAMA, but little money was raised, and NIH Institutes were then taxed to provide funds for this program. NICHD established, in accordance with the BPCA legislation, a program to conduct a prioritization process including an annual meeting to identify off-patent drugs and therapeutic areas that needed study. WR’s that had been turned down by industry were also included in the prioritization process. The other two mandates, to sponsor pediatric clinical studies and submit the data to FDA for labeling considerations, were fulfilled, as well. Pediatric subspecialists prioritize drugs to study, after which the NICHD and FDA makes a final priority list, published in the Federal Register. The final list reflects the need for pediatric studies based on therapeutic gaps such as the frequency of prescribing and the disorder being treated, potential health benefits, and the availability of infrastructure to support studies. This process was not perfect, and the path to labeling was not clear. FDA would send a Written Request to NICHD for a product to be studied, after which NICHD would have to invite proposals and then select the group to conduct the study. This process was not very efficient and the lack of pediatric endpoints created additional trial design issues. Little progress was made in the study of off-patent drugs until an approach was developed by Dr Anne Zajicek and colleagues at NICHD with input from Dr Dianne Murphy and other pediatricians at the FDA. Furthermore, the law required all the data to be submitted to FDA’s Docket and this process had to be developed. Because the sponsors still own the label, negotiations between FDA and the sponsor concerning the new information that resulted from the requested studies had to be negotiated. In 2010, a model pediatric product development trial network was established, the Pediatric Trials Network (PTN), through a contract to Duke University under the leadership of Dr Daniel K. Benjamin, Jr(29) This network was specifically tasked to study off-patent drugs used routinely in children without sufficient safety and efficacy data.

Pediatric Labels for Off-Patent Drugs

The PTN has been successful at conducting trials; however, there have been additional challenges to secure pediatric labeling. The existing label for the drug is owned by the sponsor that owned the drug when it was initially approved by the FDA. In many instances, the original manufacturer for a specific drug no longer existed or had merged with other companies. NICHD and FDA worked to implement the public submission process of the trial data to FDA and have it reviewed by the FDA. The data and FDA reviews were public information. Additional activities included incorporating FDA and NICHD pediatric experts into discussions with the academic investigators. Through this BPCA program: 1) approximately 100 drugs/therapeutics and 46 conditions/indications have been prioritized, 2) 15 off-patent and 9 on-patent Written Requests have been received, and 3) 7 Proposed Pediatric Study Requests (PPSRs) have been submitted to the FDA.

Through 2016, six drugs and one device have been labeled for children under this program. This effort is accelerating with funding for 32 projects, including 22 prospective clinical trials involving 74 molecules in 12 therapeutic areas that enrolled over 6000 children at 160 sites in 5 countries. As of 2016, they have led to 7 new labels with 3 more studies pending approval by the FDA for labeling changes.(29) These studies have also identified key infrastructure needs for all aspects of clinical trials of medications in the pediatric population, including: site management; training of investigators and site staff, study design incorporating pediatric clinical pharmacology; local attitudes that support recruitment; age appropriate and palatable formulations; knowledgeable data analysis for studies in small populations; and knowledge of the requirements for device development and validation. The need to coordinate these trials on an International level is particularly problematic for rare diseases and diseases where both adults and children have the condition but children are a small proportion of that population. However, the label changes indicate this program is accelerating and needs continued support to evaluate the numerous older drugs that are frequently used in pediatric clinical care. This provision of BPCA was not made permanent in 2012 and must be renewed in 2017 if the pediatric study and labeling of older drugs is expected to continue.

PREA and BPCA 2002, 2007, 2012

Both PREA and BPCA were renewed every 5 years as parts of various FDA laws until 2012, when they were made permanent except for a few provisions. Each earlier renewal added different functions to improve the process for pediatric studies, but they maintained both the BPCA voluntary incentive program and the PREA requirement for pediatric studies of new drugs. A FDA pediatric review committee (PERC) was established in 2002 to provide pediatric expertise to study plans that may be developed by divisions with little or no pediatric input. By the end of 2016, these legislative changes led to 665 label changes that included new pediatric prescribing information. Initially most studies of medications in children leading to label changes occurred in response to the WRs issued through FDAMA and BPCA.(30) This changed around 2005, and most label changes since then have occurred in response to the requirements of PREA. Overall, FDAMA, PREA, and BPCA have increased the study of drugs in children, as reviewed by Sachs et al.(2) Among drugs that are relevant to pediatrics, 57% had adequate pediatric labeling. Unfortunately, not all pediatric populations have benefited equally from these regulatory changes.

Neonates, the Ultimate Therapeutic Orphans

To better understand the impact of these legislative changes on drug therapy for the most vulnerable population, Laughon et al analyzed the studies conducted in neonates relative to the use of these medications in that population.(31) From 1997 to 2010, they found that 41 studies enrolled neonates involving 28 drugs which led to 24 label changes, representing 6% of all label changes. Although disappointing, this was not a surprise to those who study drugs in neonates. What was a surprise was the comparison of the drugs studied to the drugs used in 290 NICUs throughout the U.S. caring for 446,335 neonatal patients. Among the 28 drugs studied in neonates, 13 were never used to treat neonates and 8 were used in less than 0.013% of NICU patients. Only 7 studied drugs were actually used in the NICU. Even though the studies of medications had satisfied the requirements of BPCA and/or PREA, they did not meet the needs of the neonatal population. A new approach is still needed to accelerate the study of new and existing drugs which are used in the NICU population.(32, 33)

Pediatric Patient Population vs PREA Requirements

The success of these laws has created another unanticipated consequence. PREA requires study of all new drugs in pediatric patients unless a waiver or deferral is granted. With the proliferation of new drugs for the treatment of type 2 diabetes (T2D), a recent paper describes how the pediatric population in the US with T2D may not be large enough to satisfy PREA requests in the U.S.(34) Patient data were derived from the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) Study, a survey of the Pediatric Endocrine Society, a registry of the Pediatric Diabetes Consortium and the SEARCH for Diabetes in Youth (SEARCH) study. In 2014, they estimated that there were ≤25,000 patients with T2D in the U.S. between 10 and 18 years of age. Conducting all the individual T2D studies required by regulatory agencies would require approximately 3,800 patients. The TODAY study showed that almost half of the patients with T2D don’t meet entry criteria because of a hemoglobin (Hb) A1C level < 7.0%. This highlighted the different course of T2D in adults and adolescents in whom 50% had a rise in Hb A1C from 5.9% to >8.0% during 11 months of monotherapy with metformin. The regulatory agencies have recognized this issue and published alternate approaches that might be used, including a collaborative approach by companies that allows different drugs to be compared with the same control group.(35) Another challenge in T2D studies can be seen from the first 500 patients in the registry in whom >90% were from families that might not be able to afford to take time from work to transport their children to study visits.

Another challenge relates to efforts to harmonize studies with the European Medicine Agency (EMA) and the FDA, which do not always have the same study requirements. For example, the EMA’s deadlines for completion of pediatric studies of T2D drugs have been extended to 2027. The Agencies have monthly discussions and are able to resolve differences in over 70% of the issues.(36) Finally, most diabetes care is provided at academic centers and most have been slow to give credit to their faculty who participate in industry-sponsored studies, as opposed to NIH-funded studies. Without multiple ongoing studies, academic centers struggle to maintain a pool of trained pediatric study coordinators and principal investigators who retain the interest and commitment to studies that are often slow to enroll and involve small numbers of participants. Instead they move from “feast to famine” as studies start and end. All of these factors contribute to the overall lack of pediatric studies and illustrate the challenges for industry to meet the requirements of PREA when the study population is small and the drugs to be studied are numerous.

Pharmacogenomic Challenges: The Impact of Development on the use of Genotype Data

Another challenge to pediatric drug development reflects the progress from the Human Genome Project, which identified genotypic explanations for some of the variation in pharmacokinetics and pharmacodynamics that used to be described as just “human variation.” For example, single nucleotide polymorphisms (SNPs) in various genes can explain several disorders, including: 1) severe respiratory distress syndrome in mature newborns from inadequate production of active surfactant (37, 38); 2) most cases of cystic fibrosis(39); 3) increased response of some asthma patients to specific inhaled glucocorticoids(40); and 4) reduced analgesia from recommended dosages of codeine in individuals with inactive CYP (cytochrome P450) 2D6.(41) Beyond identification of specific SNP’s that relate to pediatric therapy, variation among drug metabolizing enzymes in their extent and timing of maturation present unique pediatric challenges. The major classes of Phase I, hepatic CYPs mature at different rates.(42) At some ages, the activity of these enzymes normalized to body weight can be twice as high as the same enzyme activity in an adult while another enzyme may have only half of adult activity. A clinical trial that includes children from infancy to adolescence often must determine the pharmacokinetics in several different age ranges depending on the mechanism of disposition and whether it involves CYPs that develop slowly during infancy and childhood.

FDA Guidance for Pediatric Studies of Drugs and Biologicals vs Neonates

In December 2014, the FDA issued General Clinical Pharmacology Considerations for Pediatric Studies for Drugs and Biological Products Guidance for Industry.(14) This guidance outlined how to study drugs in children, but it provided minimal information about how to study drugs in neonates. In response to this problem, the International Neonatal Consortium (INC) was formed (43) and convened an expert panel to determine optimal approaches to study drugs in neonates.(43, 44) This consortium has benefited from input from regulators in the U.S., Europe, Canada and Japan along with parents, neonatal nurses, neonatologists, clinical pharmacologists, pharmacometricians, ethicists, and pediatricians from industry. The FDA acknowledges and supports such collaboration if neonatal clinical trials are to be successful.(45)

Challenges with Pediatric Studies of Drugs

FDAMA, BPCA and PREA, have achieved significant gains for pediatric studies of medications with over 600 products studied in the pediatric population.(46) They have proven that studies can be conducted ethically, safely and effectively in pediatric patients. However, when these studies are examined in detail, they are mostly inefficient and costly. Sites and study sponsors often struggle with both enrollment and retention of pediatric study patients, sometimes unable to enroll a single patient. Although pediatric medical subspecialists have important expertise regarding specific diseases and their treatment and may have access to considerable numbers of patients with the condition intended for study, they may not have clinical research expertise and/or their institutions often lack an appropriate infrastructure for conducting pediatric clinical trials. Contract completion, IRB approval and enrollment all take longer in most pediatric studies, adding to their costs and delays completion. Once started, study protocols often have to be amended which further adds to the cost.

Additional problems include a lack of adequate financial support from industry over the last decade. Many aspects of clinical trial conduct have been transferred from the sponsor to clinical sites, including source document development, electronic data entry, increased regulatory requirements, remote monitoring, and increased training requirements with duplication among sponsors (eg, Good Clinical Practice required by each sponsor rather than a generally accepted module that can meet the need of all sponsors). A new approach is urgently needed and there is a potential solution in development.

AAP and Other Key Stakeholders Catalyze New Approaches to Study Drugs in Children through the Critical Path Institute

In November, 2014, the AAP along with several other collaborative groups convened a meeting, The Pediatric Clinical Trials Stakeholder Forum, to discuss the need for pediatric drug studies and to identify ways to address this deficiency.(47) The AAP was supported in this effort by parent advocacy groups, BIO, NIH, March of Dimes, PhRMA, and pediatricians from industry to conduct a truly multidisciplinary meeting. Input was provided by nurses, parents, pediatricians, clinical pharmacologists, pediatricians from industry, and leaders from the NIH and the FDA.

In response to the Critical Path Initiative implemented by the FDA in 2005, a non-profit organization called the Critical Path Institute was created by scientists who had worked at the NIH and the pharmaceutical industry (https://c-path.org/). Their goal was to bring together scientists from the FDA, industry and academia to collaborate and improve drug and device development and regulatory processes for medical products.(45) The Critical Path Institute provided organizational input to the Stakeholder Forum and infrastructure support to guide the development of effective groups to achieve the goals identified at the Forum. After the 2014 Stakeholder meeting, the Critical Path Institute organized the International Neonatal Consortium (INC) (43) and the Pediatric Trials Consortium (PTC) to facilitate neonatal and pediatric drug development. Within the INC, groups of experts from over 30 countries in neonatal medicine, regulatory science from several countries, industry, clinical pharmacology, ethics, and parents have been assembled to develop and standardize clinical trial designs in clinically challenging therapeutic areas such as bronchopulmonary dysplasia, seizures, hemodynamic adaptation, retinopathy of prematurity, and necrotizing enterocolitis. PTC developed another collaborative group of 30 diverse organizations, including clinicians, parents, patient advocates, regulators, professional societies, international experts, representatives from drug and biopharmaceutical industry and disease-focused pediatric networks. PTC has now established the Institute for Advanced Clinical Trials (I-ACT) for Children, a 501c3 non-profit organization to advance clinical trials of medications and devices exclusively in children.(48) This new entity will work to improve the efficiency and feasibility of pediatric clinical trials through collaboration with public and private stakeholders. It aims to shorten the time required to bring innovative drugs and devices to the care of children globally.(49) Each of these groups is leading efforts to increase clinical trials in pediatric patients

The Clinical and Translatio nal Science Awards (CTSA) Program’s Ro le in Pediatric Studies o f D rugs

The work of these two Critical Path Institute consortia are complemented by the CTSA Program that supports 62 sites to work collaboratively to improve the quality and efficiency of translational research with a focus on special populations such as children.(50) The CTSA sites are organized into themes that include the development of new and existing therapeutics for pregnant women, infants, children, and adolescents. These activities are aligned with the missions of the National Center for Advancing Translational Sciences (NCATS) (www.ncats.nih.gov/ctsa.html) and are advancing clinical trials of medications in children through infrastructure support and optimization of clinical trial processes. Establishing a full service “Trial Innovation Network” to conduct studies in special populations such as infants and children is being well supported.

The Newest Pediatric Clinical Trial Network

In 2016, the NIH developed a new initiative, the Environmental Influences on Child Health Outcomes (ECHO) program.(51) A goal of ECHO was to leverage NIH-funded institutions that are part of the IDeA program to build the IDeA States Pediatric Clinical Trials Network (ISPCTN). The goal of this new network is to provide medically underserved and rural populations with access to state-ofthe-art clinical trials from relevant pediatric cohorts. The ISPCTN has named several priority areas for study: 1) pre-, peri- and postnatal populations; 2) children with neurodevelopmental disorders; 3) infants and children with pulmonary diseases and 4) pediatric patients with obesity. Another objective of the ISPCTN is to increase research capacity at a national level through enhanced professional development of faculty-level pediatricians and affiliated professionals in clinical trials research.(51) It is anticipated that the first ISPCTN-initiated clinical trials, which includes investigations of a host of interventions (including drugs and biologics) will be initiated in 2017.

Pediatric Studies of Medications are Making Progress

As can be seen in the Figure, the study of drugs in pediatric patients has moved forward especially in recent years, but faster in some populations and in some therapeutic areas than in others. Several challenges remain, including establishing better infrastructures at study sites and greater recognition by academic institutions of the importance of these studies to the advancement of pediatric medical care. The current permanent laws, BPCA and PREA are essential, but revisions of the current legislation or new innovations will be needed to address the challenge of studying drugs in sick newborns, especially those at the extremes of prematurity. New incentives may be needed along with identification of which drugs are most in need of study. Organizational support for such studies is developing through INC, I-ACT, ISCPTN, and CTSA sites. More funding and trained investigators will be needed to provide pediatric drug therapy with as strong an evidence base as that provided for adults. Harnessing the energy of parents and listening carefully to their input along with that of nurses and children will move these studies forward in an effective and constructive way.

Figure:

Timeline for major changes in the study of drugs in children