The Revolution in Pediatric Drug Development and Drug Use: Therapeutic Orphans No More

Abstract

This lecture was given by Dr. Burckart in association with presentation of the 2014 Sumner J. Yaffe Lifetime Achievement Award in Pediatric Pharmacology and Therapeutics, which is selected by the Pediatric Pharmacy Association.

Multiple factors make conducting drug studies in the pediatric population difficult, resulting in a historic lack of information surrounding safe and efficacious drug dosing in children. The paradigm in pediatric drug development has shifted from normal science being that children are therapeutic orphans in the drug development system, to a model drift caused by pediatric legislation, to a model crisis caused by failed pediatric drug development trials, to finally a model revolution that includes pediatric patients routinely in drug development. Major regulatory actions and the accumulation of scientific evidence has created an environment where clinicians can expect properly labeled drug usage information for the pediatric population.

Introduction

Revolutions change the world, and they change concepts about the world around us. That is what Thomas Kuhn was thinking in his classic 1962 treatise on “The Structure of Scientific Revolutions.”¹ Kuhn described a process where we move from what is considered “normal science” to a model in crisis, and then to a revolution with the final result being a paradigm change. The change in pediatric drug development over the past 50 years has been no less than a complete scientific revolution. Such a revolution is always difficult to see when you are in the middle of it, and we are in fact just in the middle of the pediatric drug development and drug use revolution. Scientific revolutions are easier to see in the light of historical changes, so this presentation will dwell heavily on pediatric drug use from a historical perspective.

A presentation that spans both history and modern-day pediatric drug development is perfect for a presentation honoring Sumner Yaffe, because Yaffe played such an important part in it. Yaffe started conducting pediatric trials when few others would take on this challenge. Conducting adequate and well-controlled clinical trials in pediatrics has always been a difficult process for many reasons: ethical concerns, small population size leading to issues in recruitment, the danger of permanent damage to developing bodies, and the physiological changes throughout pediatric development causing variable effects on pharmacological response.² Faced with such difficulties, clinicians have grappled with the issue of how to effectively treat children with medications designed for adults. Multiple factors came together in 1963 to cause Harry Shirkey to dub children as “therapeutic orphans,”³ from the major lack of pediatric drug information.

Today, the combination of legislative acts and growing bodies of evidence have created a robust scientific and regulatory framework to ensure new and historic medical therapies are routinely evaluated in pediatric populations. This revolutionary change is described in the following sections and in Figure 1.

Figure 1.

Depicture of the revolution in pediatric drug development.

Prescience: Early History of Pediatric Drug Development

The first documented case of pediatric medicine was Edward Jenner's smallpox vaccination of an 8-year-old boy in 1796,⁴ yet major legislation in the United States related to the regulation of drugs did not truly begin until a hundred years after, beginning with the 1906 Pure Food and Drug Act.⁵ The 1906 Act was enacted to prevent “adulterated” and “misbranded” drugs from entering the market, specifically those containing alcohol, cocaine, and other known dangerous substances. Yet the Act could only stop “adulterated” drugs and was ultimately proven ineffective when unable to remove Dr Johnson's Mild Combination Treatment for Cancer, a fraudulent cancer cure, from the market.⁶

Major legislative action did not occur for another 3 decades until the 1937 Elixir of Sulfanilamide tragedy⁷ led to passage of the Federal Food, Drug, and Cosmetic (FD&C) Act of 1938.⁸ Sulfanilamide was dissolved in diethylene glycol, an antifreeze component known to be toxic to the kidneys, to create a palatable syrup. The resulting product, Elixir of Sulfanilamide, was sold across the country and resulted in the death of 107 patients, primarily children, spurring outrage and hastening passage of the FD&C Act.

The Food Drug and Cosmetic Act⁸ required medications to be proven safe before entering the market and empowered the FDA to oversee enforcement of the act. Twenty-five years later, disaster struck children again as thalidomide, a proclaimed “wonder drug for insomnia, coughs, colds and morning sickness,” caused the severe birth defect, phocomelia, in women who ingested the drug.⁹ As a result, tens of thousands of children were born with birth defects directly related to thalidomide, but the drug never gained FDA approval in the United States at the time. Frances Kelsey, a young medical officer at the FDA during the time of these events, resisted pressure both from the pharmaceutical industry and from within the Agency to approve thalidomide in the United States.¹⁰ Unsure of the safety of the drug, Kelsey refused and thereby spared US children from this debilitating birth defect. President John Kennedy conferred the President's Award for Distinguished Federal Civilian Service on Dr Kelsey in 1962.

Outrage following the thalidomide scare directly led to the 1962 Kefauver-Harris Amendments,¹¹ requiring companies to prove their products to be safe and effective using “adequate and well-controlled studies” and established informed consent in drug trials. A small number of the new drugs had potential for use in children, yet many companies chose to avoid clinical studies in the pediatric population, appending their labels with an “orphaning” clause, not to be used in children.¹²

Normal Science: Pediatric Patients Described as Therapeutic Orphans

“By an odd and unfortunate twist of fate, infants and children are becoming ‘therapeutic or pharmaceutical orphans.'” At the June 1963 Conference of Professional and Scientific Societies in Chicago, sponsored by the Commission on Drug Safety, Harry Shirkey declared infants and children as “therapeutic orphans.” The prevailing attitude for pediatric drug development was of low profitability, from anticipated small sales volume to the difficulty of recruiting experienced clinical investigators and patients for the study.¹² The climate was that of a double standard; adults were treated in accordance with an established and labeled usage, but pediatric patients were treated without either.

The Kefauver-Harris Amendments were enacted to protect study subjects but also increased reluctance of the medical field to conduct clinical trials in pediatric patients. The pediatric population is more vulnerable to unpredictable adverse effects, yet with less testing and information available. The paradoxical outcome was increased danger to this vulnerable population, as the lack of routine pediatric information meant most were treated off-label, with physicians ignoring the warning “not to be used in children” and utilizing the restricted drugs.

Multiple sources validated the therapeutic orphan model. From “An Update on the Therapeutic Orphan” by John Wilson in 1999,¹³ 78% of 2000 drugs from the 1973 Physicians' Desk Reference (PDR) was found to be without pediatric labeling or sufficient use information for children. Twenty years later, 81% of the drugs listed in the 1991 PDR had disclaimers or age restrictions, indicating the longstanding nature of the problem. The lack of pediatric labeling was also reflected in the approval of new molecular entities (NMEs): 80% of NMEs in 1984–1989, 79% of NMEs in 1992, and 71% of NMEs in 1991–1994 were without pediatric drug labeling.

Yet many drugs were prescribed for the pediatric population, despite the lack of pediatric labeling. An analysis of off-label prescribing of 11 drugs with pediatric age disclaimers found high off-label frequency. Some highlights, from an FDA Pediacom analysis of Intercontinental Marketing Statistics survey of outpatient prescribing by 2940 physicians across 7 specialties, included 1,626,000 albuterol inhalation solution prescriptions in ages <12 years, 663,000 Phenergan in <2 years, 248,000 Zoloft, 349,000 Prozac in <12 years of age. Thus, the problem of the therapeutic orphan lies in both drug reference sources, such as the PDR, and in actual use of prescription drugs in children.¹³

Model Drift: Promotion of Pediatric Drug Development Through Legislation

In 1974, Congress passed the National Research Act,¹⁴ which created the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, to identify basic ethical principles to be followed when conducting biomedical and behavioral research on human subjects and develop guidelines in accordance with the identified principles. Also, in 1974 the FDA commissioned the AAP Committee on Drugs to develop “General Guidelines for the Evaluation of Drugs to be Approved for Use during Pregnancy and for Treatment of Infants and Children.” Three years later, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research published their report and recommendations on “Research Involving Children” in 1977. That same year, the FDA published the pediatric guidance “General Considerations for the Clinical Evaluation of Drugs in Infants and Children” and the AAP released their Statement on Ethical Conduct of Research. In 1979, the FDA mandated that medication labels note whether safety and efficacy had been established in pediatric populations.¹⁵ These legislative acts were indicative of the great need for pediatric clinical research, but no meaningful pediatric drug development research was conducted for the next 20 years.

In an effort to increase pediatric labeling, the FDA Final Rule on Pediatric Labeling was passed in 1994,¹⁶ which allowed labeling of drugs for pediatric use based on extrapolation of efficacy in adults and additional pharmacokinetic (PK), pharmacodynamic (PD), and safety studies in pediatric population. The 1997 FDA Modernization Act (FDAMA)¹⁷ provided the additional incentive of 6-month patent exclusivity for companies who voluntarily conducted pediatric trials on their product. Although FDAMA provided some financial incentive, few manufacturers chose to conduct pediatric studies, as the potential profit from 6 months of patent exclusivity was not considered adequate compensation for the costs of running those studies. The timeline for pediatric legislative acts is presented in Figure 2.

Figure 2.

Timeline of major US legislation related to pediatric drug development.

It was not until passage of the Best Pharmaceuticals for Children Act (BPCA)¹⁸ and Pediatric Research Equity Act (PREA)¹⁹ in 2002 and 2003, respectively, that pediatric studies became widespread. BPCA identified drugs in need of further study, prioritized a list of drugs, and sponsored relevant pediatric trials through increased funding via the National Institutes of Health. Furthermore, BPCA allowed the FDA to issue Written Requests, creating a means of voluntarily requesting pediatric clinical studies outside of existing framework. PREA required all new drug applications, biologic licensing applications, and supplements submitted for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration to contain a pediatric assessment, unless the assessment was waived or deferred until a later date.²⁰ The 2 acts together added information concerning the safe and effective use of more than 400 drugs in neonates, infants, children, and adolescents within the first 5 years of implementation. Originally set to expire after 5 years, the overwhelming successes of BPCA and PREA led to the 2007 FDA Authorization Act (FDAAA),²¹ which renewed the 2 acts for another 5 years. Through advocacy efforts, BPCA and PREA became permanent in 2012 with the FDA Safety and Innovation Act (FDASIA).²²

Continuing the trend of addressing therapeutic gaps, the FDA expanded pediatric clinical trial requirements in pediatric oncology, beginning with passage of the FDA Reauthorization Act (FDARA) in 2017.²³ FDARA included the Research to Accelerate Cures and Equity for Children Act²⁴ effective August 2020, which requires new oncologic agents indicated for adult cancers to conduct pediatric studies if that agent could potentially be used for pediatric cancers based upon the molecular target of the drug, not the drug's adult indication.²⁵ FDARA also plugged the orphan drug loophole, removing orphan drug exemption for cancer drugs related to pediatric diseases. Conducting pediatric oncology trials is additionally challenging because it shares the same difficulties as general pediatric medicine but intensified. Pediatric cancers have higher relative rarity compared with adult cancers, combined with differences in etiology and development, providing another level of complexity to the already complex pediatric patient.²⁶ Furthermore in response to the lack of pediatric patients in oncology clinical trials, the FDA released the 2019 Guidance on Considerations for the Inclusion of Adolescent Patients in Adult Oncology Clinical Trials to help facilitate the inclusion of adolescents in adult oncology studies to promote pediatric labeling at the time of marketing authorization for adults.²⁷

Model Crisis: Failed Pediatric Trials

Conducting a successful clinical trial for the pediatric population is difficult due to multiple factors. These factors can roughly be divided into disease factors and pharmacologic factors. Determining whether a pediatric disease is the same as an adult disease may seem simple, particularly for many infectious diseases. However, it is much more difficult for other diseases where symptomatology is the same, yet the underlying pathophysiology is quite different. Pharmacologic factors can also be complex. Physiologic differences in metabolizing enzymes, receptors, transporters, body surface area, and weight all affect PK and PD properties, often creating unexpected dose-response curves in the pediatric patient versus the adult.²⁸

Pediatric drug development trials had a high failure rate for the first decade following FDAMA in 1997. Forty-two percent of pediatric studies performed under BPCA from 1998 to 2012 failed to achieve an indication for use in pediatric patients.²⁹ Dosing was identified as a contributing factor for trial failures, leading to 10 cases of trial failure due to lack of efficacy.³⁰ The 2 most common dosing issues were not testing a range of doses and limiting pediatric drug exposure to that which has been shown to be efficacious in adults for a clinically distinct disease. As stated previously, the adult efficacious dose may not be appropriate for pediatric patients for many reasons.

The case of pediatric neurogenic bladder dysfunction (NBD) drug development illustrates the difficulties of drug development of a pediatric disease that has a different underlying etiology and pathophysiology compared with the adult disease.³¹ NBD is a heterogenous diagnosis that broadly describes bladder dysfunction caused by injury affecting innervation of the lower urinary tract. Differences are particularly notable in the etiology and presentation of non-traumatic NBD in children and adults. Non-traumatic NBD in children is most commonly caused by congenital neural tube defects, whereas adult non-traumatic NBD is most commonly acquired by infection or diseases of the central or peripheral nervous systems. Several antimuscarinic and α 1-receptor antagonist drugs approved in adults for either overactive bladder (OAB) or benign prostatic hyperplasia have been evaluated in pediatric NBD: oxybutynin, tolterodine, tamsulosin, and alfuzosin. Of these 4 agents, only oxybutynin received FDA approval for treatment of pediatric patients. The scientific rationale for using tolterodine, tamsulosin, or alfuzosin for treatment of pediatric NBD was established, but the lack of pediatric use approval was due to trial failures. Though the exact reasons for trial failure are unknown, there are multiple changes that would have significantly increased the chance of trial success. All 4 pediatric NBD drug development programs targeted drug exposures to approximate levels that were efficacious in adults for OAB and benign prostatic hyperplasia. However, it was not clear that the adult exposure levels were efficacious in pediatric NBD. Furthermore, PK sampling during the completed trials confirmed that drug exposures in pediatric patients were often below the targeted adult exposures. Exploring dose optimization before the phase 3 trials may have been helpful, particularly to establish if the targeted adult exposure was effective in pediatrics, as higher doses may have been necessary. Oxybutynin was the only development program that adjusted dose (based on tolerability and effectiveness at the investigators' discretion) throughout the trial, and the majority of pediatric patients received doses greater than or equal to the adult starting dose for OAB. Overall success rates could be improved through enrichment strategies, to help overcome the inherent difficulties in conducting trials in a small patient population with high interpatient variability.

Model Revolution: Overcoming Drug Development Problems

Decades of clinical research have yielded multiple strategies to address each of the obstacles in pediatric drug development. At the risk of oversimplification, the major hurdles in pediatric drug development can be divided into 4 areas: ethical concerns, small population size, difficulty finding an optimal dose, and overall trial design and failure rate.

Ethical Issues. “The Commission recognizes, however, that the vulnerability of children, which arises out of their dependence and immaturity, raises questions about the ethical acceptability of involving them in research. Such ethical problems can be offset, the Commission believes, by establishing conditions that research must satisfy to be appropriate for the involvement of children.” – National Commission 1978.

Every subject in a research study is undertaking some risk, be it receiving placebo or experiencing adverse effects of the treatment, but the pediatric population is especially vulnerable. Medically, children and infants are at increased risk of adverse events and side effects for even therapies proven safe in other age groups. There is also the risk of permanent damage to developing bodies, a risk generally not present in adult patients. Furthermore, the pediatric population is generally dependent on other adults for care and are themselves at varying levels of maturity, limiting their ability to understand the ramifications of investigative agents and adhere to study requirements. Therefore, multiple safeguards are necessary to ensure research in pediatric patients is conducted ethically.

The first set of safeguards were those universal for any participant in a clinical trial. These meant informed consent and adequate, well-controlled trials through the 1962 Kefauver-Harris Amendments and the concepts of respect for persons, beneficence, and justice through the 1979 Belmont Report. Though these requirements were mainly geared toward adults, they set the base work for protection for children. The second major safeguard was refining the meaning of “informed consent” when applying to children. Because pediatric patients do not generally have the legal capacity to provide informed consent, the concepts of parental permission and child assent have been developed as standards for ethical research in children. Third was defining the criteria for necessary pediatric studies. The Report and Recommendations on Research Involving Children issued by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research in 1978³² specified studies that represented “minor increase over minimal risk” and “scientific necessity” were ethically justifiable. Later amendments expanded to allow “greater than minimal risk, no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about subjects' disorder or condition” to avoid excluding potentially useful research that did not immediately fall under “minor increase over minimal risk.” PREA also specified that pediatric studies only be initiated if the therapy represents a “meaningful therapeutic benefit.” Thus, multiple safeguards are in place to protect pediatric patients while allowing investigative drug trials in children to be conducted ethically.

Pediatric Patient Population. Small populations are a major hurdle in clinical research. A small population makes patient recruitment into clinical trials difficult, as the overall pool to draw potential subjects from is limited. A modest sample size weakens the data, from the robustness of the statistical analyses to the potential extrapolation of the results to the general population. Two strategies that can be used to deal with small population sizes are patient enrichment and master protocols.

Enrichment is “the prospective use of any patient characteristic to select a study population in which detection of a drug effect (if one is in fact present) is more likely than it would be in an unselected population.”³³ Enrichment strategies discussed in the guidance are divided into 3 broad categories: 1) strategies to decrease variability, 2) prognostic enrichment strategies, and 3) predictive enrichment strategies. Variability in the study population can be decreased by choosing patients with prespecified baseline measurements, such as a disease or a biomarker characterizing the disease in a narrow range, and excluding patients whose disease or symptoms improve spontaneously or whose measurements are highly variable. The decreased variability would also provide the beneficial effect of increased study power. Prognostic enrichment strategies include choosing patients with a greater likelihood of having a disease-related endpoint event (for event-driven studies) or a substantial worsening in condition (for continuous measurement endpoints), which would increase the absolute effect difference but not relative effect difference between groups. Predictive enrichment strategies include choosing patients who are more likely to respond to the drug treatment than other patients with the condition being treated, which can lead to a larger effect size, both absolute and relative, and can permit use of a smaller study population. In almost all cases, the strategies discussed are prospectively planned and fixed prior to study initiation, and thus generally do not compromise the statistical validity of the trials or the meaningfulness of the conclusions reached for the population studied.

The enrichment strategies in pediatric drug development trials have been examined, and appear to have an important impact on the trial success.³⁴ For studies submitted to the FDA from 2012–2016, the highest pediatric trials success rates (87.5%) were associated with the use of all 3 enrichment strategies (practical, prognostic, and predictive), and the lowest success rates (65.4%) were associated with trials where no enrichment strategies were used. Therefore, the extensive use of enrichment strategies in pediatric trial design was the best route to trial and program success in pediatric drug development.

Master protocols are defined as “one overarching protocol designed to answer multiple questions.”^35,36 These protocols are often subcategorized as “basket” or “umbrella” studies depending on the study focus, that is, investigating one drug for multiple subpopulations (basket) or focusing on one disease state and testing multiple drug regimens and/or doses (umbrella). The chief advantage is the streamlining of multiple protocols into one titular master protocol, allowing use of a common screening platform, centralized shared governance, study site systems, and protocol elements. Depending on the design, the studies may utilize a shared control arm to decrease the number of patients needed. Additionally, the master protocol may make use of adaptive or Bayesian design, adding and stopping treatment arms as the study progresses to concentrate on the more effective treatment regimens identified during interim and futility analyses. These strategies can improve the success rate of any clinical trials involving small populations sizes, not just pediatric studies.

Another approach is to more efficiently use all of the information available, including adult information, to apply to understanding pediatric drug use. One approach to doing this is to use the extrapolation of efficacy from adult patients to pediatric patients. The other approach is to utilize the adult data more efficiently using Bayesian techniques, as discussed in 2019 by Hsu et al.³⁷

In 1994, the FDA Final Rule on Pediatric Labeling¹⁶ proposed an efficacy extrapolation approach, where labeling of drugs for pediatric use could be based on extrapolation of efficacy in adults combined with additional pediatric studies. Extrapolating efficacy from adult data or other data to the pediatric population can streamline drug development and help to increase the number of approvals for pediatric use. To illustrate, 137 of the 166 products submitted between 1998 and 2008 used some form of extrapolation, and partial extrapolation was the most frequent category.³⁸ As more data have been generated, the extrapolation approach used has shifted away from partial to either complete or no extrapolation. In a 2017 study, 157 products were approved for pediatric use between 2009 and 2014 where complete, partial, or no extrapolations changed from 14%, 68%, and 18% in the 2011 study to 34%, 29%, and 37%, respectively.³⁹

One of the most effective approaches to getting early pediatric labeling is to include the pediatric population in the phase 3 adult clinical trial when possible. In a 2020 report of these studies,⁴⁰ over 70 products got simultaneous approval of the drug in adults and in all or part of the pediatric population. Although adolescents are the most likely population to include in a phase 3 adult trial, orphan drug studies often included all of the pediatric population.

Pediatric Dose. Determining a safe and effective pediatric dose is still a challenge. Most drugs are originally developed for the adult population then dose adjusted for the pediatric population. Though linear scaling by weight, age, or body surface area are the main methods of estimating a pediatric dose, the dose calculated is regrettably often neither safe nor effective, due to the underlying assumption that the dose-response is linear. Empiricism has improved the accuracy of recommended doses, but the trial-and-error method is a slow and inefficient way of determining optimal pediatric dose. Pediatric dose selection is not a scientific process in 2020, but dosing science is moving toward making this more of a structured process.⁴¹

Better pediatric dose selection methods exist through the application of classical PK-PD, population PK, and physiologically based PK models. These models do not necessarily replace traditional dose-finding studies but complement and guide dosing decisions based on the additional information they provide.

An additional approach to dose finding is the more extensive use of exposure-response analyses in pediatric and adult patients during drug development today. Over 50 of these analyses have been conducted for pediatric exposure response relationships, and dosing is the primary use of these studies.⁴²

Trial Design and Overall Success. The selection of a study endpoint is crucial to trial success. Green et al⁴³ analyzed 234 pivotal pediatric efficacy trials to characterize the endpoints of trials that successfully met their primary efficacy endpoints. Trials that utilized endpoints that were the same between pediatric and adult populations fared better than trials using differing endpoints (odds ratio, 4.03). Trials that included both pediatric and adult patients in the same trial had higher success rates than those that separated them: 89.5% success (85 of 95) vs 67.6% success (94 of 134). Additional observations made were that objective endpoints performed better than subjective endpoints, with composites containing both outperforming the singular endpoints.

The use of surrogate endpoints has been successful in pediatric drug development. When compared with clinical endpoints for trials, surrogate endpoints were as successful as clinical endpoints.⁴⁴ This observation provides encouragement for the development of additional validated biomarkers in the pediatric population, which can facilitate drug development studies in smaller patient populations.⁴⁵ All of the other strategies discussed in the above paragraphs contribute to overall trial success. As the nature of pediatric clinical development problems are multifarious, a combination of the strategies discussed may ultimately be the most successful.

Paradigm Change: Modern Pediatric Drug Development Programs

The pediatric drug development landscape today is vastly different from its unregulated beginnings. Decades of research and experience have identified the problems unique to pediatric drug development and multiple methods of overcoming them. The accumulation of important legislative acts has created a robust regulatory framework to ensure all new drugs are reviewed for potential use in pediatric populations. At the same time, science has advanced so that the ontogeny of developing drug-related systems in pediatric patients is increasingly understood,⁴⁶ and pediatric trial failure rates are down to about 20%.⁴³ Though the pediatric drug development process is still difficult, there are many successful programs and the future is very positive.⁴⁷

Through BPCA, and PREA, all new drugs are reviewed for potential use in pediatric populations. Today there are more than 840 small molecule and biologic products with pediatric labeling from the results of these acts.⁴⁸ The FDA has issued many guidances during this period for pediatric drug development: General Clinical Pharmacology Considerations for Pediatric Studies for Drugs and Biological Products, FDARA Implementation Guidance for Pediatric Studies of Molecularly Targeted Oncology Drugs: Amendments to Sec. 505B of the FD&C Act, Considerations for the Inclusion of Adolescent Patients in Adult Oncology Clinical Trials Guidance for Industry, and others. As pediatric medicine continues to develop, more areas of need and their solutions will be found. The regulatory framework has ensured pediatric trials will continue to be conducted to generate labeled, approved pediatric usages.

Antibody-based therapeutic proteins is one example of an important treatment modality that has emerged during this period with the ability for a more targeted effect and potential for better safety profiles. The development of monoclonal antibodies and Fc-fusion proteins has different challenges than small-molecule drugs because different mechanisms govern the PK and PD of these proteins. One challenge is the target-mediated drug disposition, where the kinetics of the target can directly affect the PK of the drug. This mutual interdependence of PK and PD introduces nonlinearity and requires integrated modeling analysis of PK and PD data. Knowledge about these mechanisms in adults and pediatric populations is growing. In a review of the biologic products available as of March 2018, 68 products were listed in the Purple Book.⁴⁹ Of those 68, 20 had pediatric indications. With encouragement by the FDA to start pediatric trials early in the drug development process, 13 of those 20 had simultaneous adult and pediatric indication approvals. Of the 7 that did not have simultaneous approval, the lag time varied from 1 to 12 years, with an average lag time of 5.8 years. All 20 biologics with pediatric indications used modeling and simulation in their drug development programs.

Another revolutionary program is the use of modeling to predict drug concentrations in the fetus, and then concentrations in the postpartum period. Physiologically based PK has progressed to be able to make these predictions that Dr Yaffe could only imagine in the 1960s. Examples include recent publications of anti-HIV and antiviral drugs used in the mother.^{50, 51}

Conclusion

Through the combined efforts of regulatory policy and scientific research, pediatric clinical programs have become a standard component in drug development programs of all types. Though challenging, multiple strategies have been developed to overcome the various hurdles innate to pediatric medicine, so that pediatric clinicians can expect adequate and well-controlled studies of all drugs for use in pediatric patients. Neonates, pediatric oncology, and orphan diseases are the new frontiers in pediatric medicine, and the revolution in pediatric drug development will continue. But for the general pediatric population, children are “therapeutic orphans” no more.

ABBREVIATIONS

AAP

American Academy of Pediatrics

BPCA

Best Pharmaceuticals for Children Act

FDA

Food and Drug Administration

FDAMA

US FDA Modernization Act

FD&C

Federal Food, Drug, and Cosmetic

FDAAA

FDA Authorization Act

FDARA

FDA Reauthorization Act

FDASIA

FDA Safety and Innovation Act

HIV

human immunodeficiency virus

NBD

neurogenic bladder dysfunction

NME

new molecular entities

OAB

overactive bladder

PD

pharmacodynamic

PDR

Physicians' Desk Reference

PK

pharmacokinetic

PREA

Pediatric Research Equity Act

RACE

Research to Accelerate Cures and Equity