How is the Pharmaceutical Industry Structured to Optimize Pediatric Drug Development? Existing Pediatric Structure Models and Proposed Recommendations for Structural Enhancement

Correction; Early Access: DOI: 10.1007/s43441-020-00152-0 Early Access: APR 2020Background Pediatric regulations enacted in both Europe and the USA have disrupted the pharmaceutical industry, challenging business and drug development processes, and organizational structures. Over the last decade, with science and innovation evolving, industry has moved from a reactive to a proactive mode, investing in building appropriate structures and capabilities as part of their business strategy to better tackle the challenges and opportunities of pediatric drug development. Methods The EFGCP Children's Medicines Working Party and the IQ Pediatric working group have joined their efforts to survey their member company representatives to understand how pharmaceutical companies are organized to fulfill their regulatory obligations and optimize their pediatric drug development programs. Results Key success factors and recommendations for a fit-for-purpose Pediatric Expert Group (PEG) were identified. Conclusion Pediatric structures and expert groups were shown to be important to support optimization of the development of pediatric medicines.Peer reviewe

Effect on bone turnover markers of once-yearly intravenous infusion of zoledronic acid versus daily oral risedronate in patients treated with glucocorticoids

Objective. Long-term glucocorticoid use is accompanied by rapid bone loss; however, early treatment with bisphosphonates prevents bone loss and reduces fracture risk. The aim of this study was to examine the effects of two bisphosphonates, i.v. zoledronic acid (ZOL) versus oral risedronate (RIS), on bone turnover markers (BTMs) in subjects with glucocorticoid-induced osteoporosis (GIO). Methods. Patients were randomly stratified according to the duration of pre-study glucocorticoid therapy [prevention subpopulation (ZOL, n = 144; RIS, n = 144) ≤3 months, treatment subpopulation (ZOL, n = 272; RIS, n = 273) >3 months]. Changes in β-C-terminal telopeptides of type 1 collagen (β-CTx), N-terminal telopeptide of type I collagen (NTx), procollagen type 1 N-terminal propeptide (P1NP) and bone-specific alkaline phosphatase (BSAP) from baseline were measured on day 10 and months 3, 6 and 12. Results. At most time points, there were significantly greater reductions (P < 0.05) in the concentrations of serum β-CTx, P1NP and BSAP and urine NTx in subjects on ZOL compared with RIS in both males and females of the treatment and prevention subpopulations. In pre- and post-menopausal women, there were significantly greater reductions in the concentrations of BTMs with ZOL compared with RIS. At 12 months, ZOL had significantly greater reductions compared with RIS (P < 0.05) for β-CTx, P1NP, BSAP and NTx levels, independent of glucocorticoid dose. Conclusions. Once-yearly i.v. infusion of ZOL 5 mg was well tolerated in different subgroups of GIO patients. ZOL was non-inferior to RIS and even superior to RIS in the response of BTMs in GIO patients. Trial registration: ClinicalTrials.gov, http://clinicaltrials.gov, NCT0010062

The Effect of 3 Versus 6 Years of Zoledronic Acid Treatment of Osteoporosis: A Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT)

ABSTRACT Zoledronic acid 5 mg (ZOL) annually for 3 years reduces fracture risk in postmenopausal women with osteoporosis. To investigate longterm effects of ZOL on bone mineral density (BMD) and fracture risk, the Health Outcomes and Reduced Incidence with Zoledronic acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT) was extended to 6 years. In this international, multicenter, double-blind, placebocontrolled extension trial, 1233 postmenopausal women who received ZOL for 3 years in the core study were randomized to 3 additional years of ZOL (Z6, n ¼ 616) or placebo (Z3P3, n ¼ 617). The primary endpoint was femoral neck (FN) BMD percentage change from year 3 to 6 in the intent-to-treat (ITT) population. Secondary endpoints included other BMD sites, fractures, biochemical bone turnover markers, and safety. In years 3 to 6, FN-BMD remained constant in Z6 and dropped slightly in Z3P3 (between-treatment difference ¼ 1.04%; 95% confidence interval 0.4 to 1.7; p ¼ 0.0009) but remained above pretreatment levels. Other BMD sites showed similar differences. Biochemical markers remained constant in Z6 but rose slightly in Z3P3, remaining well below pretreatment levels in both. New morphometric vertebral fractures were lower in the Z6 (n ¼ 14) versus Z3P3 (n ¼ 30) group (odds ratio ¼ 0.51; p ¼ 0.035), whereas other fractures were not different. Significantly more Z6 patients had a transient increase in serum creatinine &gt;0.5 mg/dL (0.65% versus 2.94% in Z3P3). Nonsignificant increases in Z6 of atrial fibrillation serious adverse events (2.0% versus 1.1% in Z3P3; p ¼ 0.26) and stroke (3.1% versus 1.5% in Z3P3; p ¼ 0.06) were seen. Postdose symptoms were similar in both groups. Reports of hypertension were significantly lower in Z6 versus Z3P3 (7.8% versus 15.1%, p &lt; 0.001). Small differences in bone density and markers in those who continued versus those who stopped treatment suggest residual effects, and therefore, after 3 years of annual ZOL, many patients may discontinue therapy up to 3 years. However, vertebral fracture reductions suggest that those at high fracture risk, particularly vertebral fracture, may benefit by continued treatment. (ClinicalTrials.gov identifier: NCT00145327).

ZOLEDRONOVAYa KISLOTA V PROFILAKTIKE POTERI KOSTNOY TKANI U zhENShchIN POSTMENOPAUZAL'NOGO VOZRASTA S OSTEOPENIEY

Профилактика остеопоротических переломов, особенно бедренной кости и позвонков, - это важная проблема здравоохранения. Подобные переломы сопровождаются повышенным риском осложнений и смерти, поэтому эффективная стратегия их профилактики может оказать значительное влияние на заболеваемость и несколько меньшее, но существенное влияние на смертность пожилых людей. 1-3 Хотя у женщин с остепенией риск развития переломов ниже, чем у женщин того же возраста с остеопорозом, тем не менее, при отсутствии лечения у них высока вероятность развития остеопороза. Более того, большинство переломов регистрируют у пациенток с остеопенией. 4 В последних рекомендациях женщинам постменопаузального возраста с остеопенией и со средним или высоким риском переломов (оценивают с помощью валидированных методов, таких как FRAX) предлагается назначать лекарственные средства, предназначенные для лечения остеопороза. 5 Пероральные бисфосфонаты предупреждают потерю костной ткани после наступления менопаузы у женщин более молодого и старшего возраста 6-8 Однако в клинической практике многие пациентки плохо выполняют рекомендации врача и принимают пероральные бисфосфонаты в течение не более нескольких месяцев. 9 В связи с этим важное значение имеет применение эффективного препарата, обеспечивающего высокую приверженность пациенток. В клинических исследованиях доказано, что ежегодные инфузии золедроновой кислоты в дозе 5 мг в течение 3 лет снижают риск переломов позвонков, бедренной кости и внепозвоночных переломов и увеличивают МПК поясничных позвонков и бедренной кости у женщин с постменопаузальным остеопорозом. 10 Кроме того, препарат снижал риск повторных клинически явных переломов у мужчин и женщин, недавно перенесших остеопоротический перелом бедренной кости. 11 Целью данного исследования было изучение эффективности и переносимости внутривенных инфузий золедроновой кислоты в дозе 5 мг у женщин постменопаузального возраста с остеопенией. В 2-летнем исследовании изучали эффективность двух и одной инфузии препарата, чтобы оценить возможность сокращения числа инфузий для профилактики потери костной ткани

Inclusion of Pregnant and Breastfeeding Women in Research – Efforts and Initiatives

Pregnant and breastfeeding women have been rendered therapeutic orphans as they have been historically excluded from clinical trials. Labelling for most approved drugs does not provide information about safety and efficacy during pregnancy. This lack of data is mainly due to ethico‐legal challenges that have remained entrenched in the post‐diethylstilbestrol and thalidomide era, and that have led to pregnancy being viewed in the clinical trial setting primarily through a pharmacovigilance lens. Policy considerations that encourage and/or require the inclusion of pregnant or lactating women in clinical trials may address the current lack of available information. However, there are additional pragmatic strategies, such the employment of pharmacometric tools and the introduction of innovative clinical trial designs, which could improve knowledge about the safety and efficacy of medication use during pregnancy and lactation. This paper provides a broad overview of the pharmacoepidemiology of drugs used during pregnancy and lactation, and offers recommendations for regulators and researchers in academia and industry to increase the available pharmacokinetic and ‐dynamic understanding of medication use in pregnancy

Regulatory strategies for rare diseases under current global regulatory statutes: a discussion with stakeholders

Abstract Rare or orphan diseases often are inherited and overwhelmingly affect children. Many of these diseases have no treatments, are incurable, and have a devastating impact on patients and their families. Regulatory standards for drug approval for rare diseases must ensure that patients receive safe and efficacious treatments. However, regulatory bodies have shown flexibility in applying these standards to drug development in rare diseases, given the unique challenges that hinder efficient and effective traditional clinical trials, including low patient numbers, limited understanding of disease pathology and progression, variability in disease presentation, and a lack of established endpoints. To take steps toward improving rare disease clinical development strategies under current global regulatory statutes, Amicus Therapeutics, Inc. and BioNJ convened a 1-day meeting that included representatives from the Food and Drug Administration (FDA), biopharmaceutical industry, and not-for-profit agencies. The meeting focused on orphan diseases in pediatric and adult patients and was intended to identify potential strategies to overcome regulatory hurdles through open collaboration. During this meeting, several strategies were identified to minimize the limitations associated with low patient numbers in rare diseases, including the use of natural history to generate historical control data in comparisons, simulations, and identifying inclusion/exclusion criteria and appropriate endpoints. Novel approaches to clinical trial design were discussed to minimize patient exposure to placebo and to reduce the numbers of patients and clinical trials needed for providing substantial evidence. Novel statistical analysis approaches were also discussed to address the inherent challenges of small patient numbers. Areas of urgent unmet need were identified, including the need to develop registries that protect patient identities, to establish close collaboration and communication between the sponsor and regulatory bodies to address methodological and statistical challenges, to collaborate in pre-competitive opportunities within multiple sponsors and in conjunction with academia and disease-specific patient advocacy groups for optimal data sharing, and to develop harmonized guidelines for data extrapolation from source to target pediatric populations. Ultimately, these innovations will help in solving many regulatory challenges in rare disease drug development and encourage the availability of new treatments for patients with rare diseases

sj-pdf-1-ctj-10.1177_17407745221132302 – Supplemental material for Strategies to facilitate adolescent access to medicines: Improving regulatory guidance

Supplemental material, sj-pdf-1-ctj-10.1177_17407745221132302 for Strategies to facilitate adolescent access to medicines: Improving regulatory guidance by Christina Bucci-Rechtweg, Angeliki Siapkara, Kristina An Haack Bonnet, Solange Corriol Rohou, Elin Haf Davies, Martine Dehlinger Kremer, Margaret Gamalo, Carmen Moreno, Robert M Nelson and Rhian Thomas Turner in Clinical Trials</p

sj-pdf-2-ctj-10.1177_17407745221132302 – Supplemental material for Strategies to facilitate adolescent access to medicines: Improving regulatory guidance

Supplemental material, sj-pdf-2-ctj-10.1177_17407745221132302 for Strategies to facilitate adolescent access to medicines: Improving regulatory guidance by Christina Bucci-Rechtweg, Angeliki Siapkara, Kristina An Haack Bonnet, Solange Corriol Rohou, Elin Haf Davies, Martine Dehlinger Kremer, Margaret Gamalo, Carmen Moreno, Robert M Nelson and Rhian Thomas Turner in Clinical Trials</p