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A pediatric formulation workshop entitled "Pediatric Formulations: Challenges of Today and Strategies for Tomorrow" was held to advance pediatric drug product development efforts in both pre-competitive and competitive environments. The workshop had four main sessions discussing key considerations of Formulation, Analytical, Clinical and Regulatory. This paper focuses on the clinical session of the workshop. It provides an overview of the discussion on the interconnection of pediatric formulation design and development, clinical development strategy and pediatric clinical pharmacology. The success of pediatric drug product development requires collaboration of multi-disciplinary teams across the pharmaceutical industry, consortiums, foundations, academia and global regulatory agencies. Early strategic planning is essential to ensure alignment among major stakeholders of different functional teams. Such an alignment is particularly critical in the collaboration between formulators and clinical pharmacology teams.

Decision-making in drug development benefits from an integrated systems approach, where the stakeholders identify and address the critical questions for the system through carefully designed and performed studies. Biopharmaceutics Risk Assessment Roadmap (BioRAM) is such a systems approach for application of systems thinking to patient focused and timely decision-making, suitable for all stages of drug discovery and development. We described the BioRAM therapy-driven drug delivery framework, strategic roadmap, and integrated risk assessment instrument (BioRAM Scoring Grid) in previous publications (J Pharm Sci 103:3377–97, 2014; J Pharm Sci 105:3243–55, 2016). Integration of systems thinking with pharmaceutical development, manufacturing, and clinical sciences and health care is unique to BioRAM where the developed strategy identifies the system and enables risk characterization and balancing for the entire system. Successful decision-making process in BioRAM starts with the Blueprint (BP) meetings. Through shared understanding of the system, the program strategy is developed and captured in the program BP. Here, we provide three semi-hypothetical examples for illustrating risk-based decision-making in high and moderate risk settings. In the high-risk setting, which is a rare disease area, two completely alternate development approaches are considered (gene therapy and small molecule). The two moderate-risk examples represent varied knowledge levels and drivers for the programs. In one moderate-risk example, knowledge leveraging opportunities are drawn from the manufacturing knowledge and clinical performance of a similar drug substance. In the other example, knowledge on acute tolerance patterns for a similar mechanistic pathway is utilized for identifying markers to inform the drug release profile from the dosage form with the necessary “flexibility” for dosing. All examples illustrate implementation of the BioRAM strategy for leveraging knowledge and decision-making to optimize the clinical performance of drug products for patient benefit.

The focus on drug delivery for the pediatric population has been steadily increasing in the last decades. In terms of developing in vitro models simulating characteristics of the targeted pediatric population, with the purpose of predicting drug product performance after oral administration, it is important to simulate the gastro-intestinal conditions and processes the drug will encounter upon oral administration. When a drug is administered in the fed state, which is commonly the case for neonates, as they are typically fed every 3 h, the digestion of the milk will affect the composition of the fluid available for drug dissolution/solubilization. Therefore, in order to predict the solubilized amount of drug available for absorption, an in vitro model simulating digestion in the gastro-intestinal tract should be utilized. In order to simulate the digestion process and the drug solubilization taking place in vivo, the following aspects should be considered; physiologically relevant media, media volume, use of physiological enzymes in proper amounts, as well as correct pH and addition of relevant co-factors, e.g., bile salts and co-enzymes. Furthermore, physiological transit times and appropriate mixing should be considered and mimicked as close as possible. This paper presents a literature review on physiological factors relevant for digestion and drug solubilization in neonates. Based on the available literature data, a novel in vitro digestion model simulating digestion and drug solubilization in the neonate and young infant pediatric population (2 months old and younger) was designed.

The October 2015 FDA/PQRI Conference on Advancing Product Quality provided a forum for the exchange of ideas focused on drug product quality between regulatory agencies, the pharmaceutical industry, and academia. Key topics of the 2015 conference were (i) emerging regulatory initiatives; (ii) regulatory submission, assessment, and inspection; (iii) product and process development; and (iv) manufacturing, risk management, and quality assurance. Key discussion points and recommendations for each track and session have been captured. With powerful advancements in product quality encompassing regulatory, industrial, and technological elements, an era of rapidly improving pharmaceutical quality is underway. At the conference, one theme prevailed through all sessions: regulators, industry, and academia are aligned in their desire for drug product quality on behalf of the ultimate stakeholder–the patient. 3D three dimensional, ANDA abbreviated new drug application, API active pharmaceutical ingredient, ASTM American society for testing and materials, BCS biopharmaceutics classification system, BLA biological license application, CGMP current good manufacturing practice, CMA critical material attribute, CMC chemistry manufacturing and controls, CPP critical process parameters, CQA critical quality attribute, CU content uniformity, DLS dynamic light scattering, DOE design of experiment, EMA European Medicines Agency, EWG Expert Working Group, FDA Food and Drug Administration, GDUFA generic drug user fee amendments, HCl Hydrogen Chloride, ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, IND investigational new drug, IQA integrated quality assessment, IR immediate release, IR information request, ISPE International Society for Pharmaceutical Engineering, MIT Massachusetts Institute of Technology, NDA new drug application, NIPP new inspection protocols project, NIR near-infrared spectroscopy, OPQ office of pharmaceutical quality, PAI pre-approval inspection, PAT process analytical technology, PDUFA prescription drug user fee act, PHS public health service, PQRI Product Quality Research Institute, PQS pharmaceutical quality system, QbD quality by design, QMS quality management system, QRM quality risk management, QTPP quality target product profile, RPM revolutions per minute, RTRT real time release testing, SUPAC scale-up and post-approval changes, UDU uniformity of dosage units, USP U.S. Pharmacopeial Convention.

Background: Profound changes in the development and the maturation of neonates' organs and organ systems over variable periods of time potentially place neonates at increased risk and/or at different risks compared with adults or older children on exposure to pharmaceutical agents. Most studies of drugs in neonates focus on pharmacokinetic and pharmacodynamic end points and include insufficient numbers of patients to permit evaluation of safety. Only one fourth to one third of approved drugs have received adequate pediatric study to permit labeling for treatment of all appropriate pediatric populations. Objective: The initial goal of the Newborn Drug Prioritization Group was to develop a reproducible, objective process for evaluating drugs most in need of study in the neonatal population based on a universally acceptable priority ranking. The criteria would be applicable across therapeutic classes and would identify those drugs for which immediate study was most needed. Methods: Because the therapeutic requirements of the neonate are unique in comparison to older infants and children, the National Institute of Child Health and Human Development and the US Food and Drug Administration (FDA) developed the Newborn Drug Development Initiative to address the limited study of off-patent drugs in newborns. In March 2003, they convened a meeting of pediatric pharmacologists and pediatric specialists from the FDA, the American Academy of Pediatrics, the National Institutes of Health, and academic institutions to discuss how to increase the study of drugs for the newborn. One of the working groups was charged to develop generic criteria for overall prioritization of drugs for study in newborns. Because resources are limited, and not all drugs identified by the 4 clinically focused working groups can receive study at the same time, a process for priority ranking is necessary. Results: The panel identified 4 general categories containing different numbers of criteria as important for ranking drugs for priority investigation: (1) the disease and indication, including elements such as the potential for adverse outcomes, frequency in newborns, and level of evidence for treatment of newborns; (2) drug characteristics, including elements such as duration of dosing, lack of age-appropriate formulation, clinically relevant drug-drug and drug-disease interactions, and drug disposition in newborns; (3) feasibility and methodology for newborn studies, including both analytical considerations and clinical end points; and (4) the ethical basis for study, including elements to address benefit or harm due to exposure to the study drug, study methodology, and benefit of the new treatment relative to established standard therapy. Based on these categories, a list of criteria to warrant study of a drug in newborns was developed. Conclusion: A process for judicious use of limited resources to rectify these deficiencies remains an urgent public health need.

The biopharmaceutics risk assessment roadmap (BioRAM) optimizes drug product development and performance by using therapy-driven target drug delivery profiles as a framework to achieve the desired therapeutic outcome. Hence, clinical relevance is directly built into early formulation development. Biopharmaceutics tools are used to identify and address potential challenges to optimize the drug product for patient benefit. For illustration, BioRAM is applied to four relatively common therapy-driven drug delivery scenarios: rapid therapeutic onset, multiphasic delivery, delayed therapeutic onset, and maintenance of target exposure. BioRAM considers the therapeutic target with the drug substance characteristics and enables collection of critical knowledge for development of a dosage form that can perform consistently for meeting the patient's needs. Accordingly, the key factors are identified and in vitro, in vivo, and in silico modeling and simulation techniques are used to elucidate the optimal drug delivery rate and pattern. BioRAM enables (1) feasibility assessment for the dosage form, (2) development and conduct of appropriate "learning and confirming" studies, (3) transparency in decision-making, (4) assurance of drug product quality during lifecycle management, and (5) development of robust linkages between the desired clinical outcome and the necessary product quality attributes for inclusion in the quality target product profile.

The advances in pharmaceutical sciences and technology have been so significant that Peter Drucker’s quote that “the future has already happened” applies readily for medicines developed for adults. For pediatric patients, the future is about to happen. The continuation of focused partnerships and knowledge sharing and leveraging are critical to ensure that pediatric patients have timely access to high quality drug products that were developed with pediatric patients in mind. An overview of regulatory efforts, regulations and legislation to address the challenges for pediatric drug development are discussed. The implementation of regulatory incentives, the Pediatric Rule, Best Pharmaceuticals for Children Act, and Pediatric Research Equity Act, is having an impact and has led to incorporation of information for dosing of approximately 500 drug products since 1998 starting with implementation of the Pediatric Rule. There are significant accomplishments and a lot more work ahead for the pediatric community. The labeling information is usually for older pediatric patients and the need for information for safe and effective dosing of patients of 6 years old or younger remains. Some of the study outcomes are inconclusive with respect to safety and efficacy, and support the hypotheses that better understanding of drug delivery to pediatric patients is needed for determining and delivering the right dose to the pediatric patients. The 2012 Food and Drug Administration Safety and Innovation Act and implementation of Quality by Design paradigm focusing on drug product design and manufacturing process are expected to have a synergistic effect for continuing to advance development of pediatric dosage forms and formulations for the benefit of the pediatric patients.

OBJECTIVE. The goal was to review the impact of pediatric drug studies, as measured by the improvement in pediatric dosing and other pertinent information captured in the drug labeling. METHODS. We reviewed the pediatric studies for 108 products submitted (July 1998 through October 2005) in response to a Food and Drug Administration written request for pediatric studies, and the subsequent labeling changes. We analyzed the dosing modifications and focused on drug clearance as an important parameter influencing pediatric dosing. RESULTS. The first 108 drugs with new or revised pediatric labeling changes had dosing changes or pharmacokinetic information (n = 23), new safety information (n = 34), information concerning lack of efficacy (n = 19), new pediatric formulations (n = 12), and extended age limits (n = 77). A product might have had ≥1 labeling change. We selected specific examples (n = 16) that illustrate significant differences in pediatric pharmacokinetics. CONCLUSIONS. Critical changes in drug labeling for pediatric patients illustrate that unique pediatric dosing often is necessary, reflecting growth and maturational stages of pediatric patients. These changes provide evidence that pediatric dosing should not be determined by simply applying weight-based calculations to the adult dose. Drug clearance is highly variable in the pediatric population and is not readily predictable on the basis of adult information.

A four-way cross-over study was performed to assess the temporal effect of food on the rate and extent of tacrine (Cognex, THA) absorption after drug administration to healthy, older volunteers. Each volunteer received four single 40-mg THA doses at 1-week intervals. Doses were administered after an 8-hour overnight fast, 1 hour before a standard breakfast, 15 minutes after beginning a standard breakfast, and 2 hours after completion of a standard breakfast. Gastrointestinal side effects were most frequently reported after drug administration to fasted subjects. Mean Cmax and AUC(0-infinity) values after THA administration during breakfast (9.9 ng/mL and 70.2 ng.hr/mL) and 2 hours after breakfast (11.6 ng/mL and 74.2 ng.hour-1.mL-1) were significantly lower than values determined after administration of THA to fasting subjects (15.8 ng/mL, and 91.8 ng.hour-1.mL-1). Little effect was evident when THA was administered 1 hour before breakfast.

The steady-state multiple-dose pharmacokinetics of tacrine were evaluated in twelve patients (mean age = 77 years) with Alzheimer’s Disease. Each patient sequentially received nine doses of 10, 20 and 30 mg of tacrine every 6 hours. Plasma tacrine concentrations were measured using a specific, validated HPLC method. Mean maximum plasma concentrations (Cmax) were 5.09, 20.7, and 33.9 @ml following the 10, 20 and 30 mg tacrine doses, respectively. Corresponding values for area under the curve (AUC) were 19.8, 83.7 and 141 ng/hr/ml. Dose normalized Cmax and AUC values determined following administration of 20 and 30 mg doses of tacrine were significantly greater (p < .05) than those after 10 mg of tacrine. Tacrine elimination half-life was approximately 3.4 hours at all dose levels. Dose-dependent increases in Cmax and extent of tacrine systemic bioavailability observed in patients with Alzheimer’s Disease were similar to those reported previously in healthy young volunteers. Saturable first-pass hepatic metabolism may be responsible for dose-dependent tacrine kinetics.