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Deriving pediatric doses for locally acting drugs (LADs) presents a unique challenge because limited systemic exposure hinders commonly used approaches such as pharmacokinetic matching to adults. This study systematically evaluated drug development practices used for pediatric dose selection of LADs approved by the U.S. Food and Drug Administration from 2002 to 2020. The three study objectives were: (1) to determine the dose selection approach for the labeled pediatric dose, (2) to examine the studied pediatric dose(s), and (3) to evaluate the characteristics of the pediatric clinical programs used to support the labeled pediatric dose. A total of 187 pediatric submissions were characterized for the labeled and studied pediatric doses of LADs. The pediatric dose was predominantly labeled as a flat dose (91%) and at a single-dose level (67%) similar to adults. The majority (68.4%) of the submissions had the same labeled dose for pediatrics and adults. Independent pharmacodynamic/efficacy studies in pediatric patients commonly (64.2%) provided supportive evidence for the labeled pediatric dose. Inhalation, nasal, and injectable submissions had the highest number of clinical trials, lowest usage of an extrapolation of efficacy approach, and utilized diverse approaches in selecting the studied pediatric doses. This article highlights approaches for LAD dosing in pediatric patients and can be used to inform drug development of these products in the pediatric population., (© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Clinical trials are an integral aspect of drug development. Tremendous progress has been made in ensuring drug products are effective and safe for use in the intended pediatric population, but there remains a paucity of information to guide drug dosages in pediatric patients with obesity. This is concerning because obesity may influence the disposition of drug products. When pediatric patients with obesity are not enrolled in clinical trials, dosing options for use in this subpopulation may be suboptimal. Reliance on physiological-based dosing strategies that are not informed by evaluation of the pharmacokinetics of the drug product could lead to under- or over-dosing with ensuing therapeutic failure or toxicity consequences. Thus, representation of pediatric patients with obesity in clinical trials is crucial to understand the benefit-risk profile of drug products in this subpopulation. It is important to acknowledge that this is a challenging endeavor, but not one that is insurmountable. Collective efforts from multiple stakeholders including drug developers and regulators to enhance diversity in clinical trials can help fill critical gaps in knowledge related to the influence of obesity on drug disposition.

Clinical pharmacology is an integral discipline supporting the development, regulatory evaluation, and clinical use of drugs for the treatment of both common and rare diseases. Here, we evaluated the recommendations and information available from select clinical pharmacology studies in the therapeutic product labeling of new molecular entities (NMEs) approved from 2017 to 2019 for both common and rare diseases. A total of 151 NMEs, including 72 orphan and 79 non-orphan drugs, were analyzed for recommendations and information available related to food-drug interaction, drug-drug interaction, renal impairment, hepatic impairment, QT assessment, and human radiolabeled mass balance studies using data collected from the original labeling and other regulatory documents. The analysis showed no statistically significant difference in the recommendations between orphan and non-orphan drugs except for renal impairment related recommendations in section 8 of the labeling. Although not significant, fewer hepatic impairment labeling recommendations were available for orphan drugs when compared with non-orphan drugs. At the time of initial approval, 79 postmarketing requirements (PMRs) and postmarketing commitments (PMCs) for 33 orphan drugs and 39 PMRs and PMCs for 19 non-orphan drugs were established; with most difference observed for drug-drug interaction, hepatic impairment, and QT assessment. Overall, although there was a trend for more labeling recommendations and fewer postmarketing studies and clinical trials for non-orphan drugs, there appeared to be no substantial differences in how these select clinical pharmacology studies are leveraged during the development and approval of orphan and non-orphan drugs., (Published 2022. This article is a U.S. Government work and is in the public domain in the USA. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Quantitative systems pharmacology (QSP) has been proposed as a scientific domain that can enable efficient and informative drug development. During the past several years, there has been a notable increase in the number of regulatory submissions that contain QSP, including Investigational New Drug Applications (INDs), New Drug Applications (NDAs), and Biologics License Applications (BLAs) to the US Food and Drug Administration. However, there has been no comprehensive characterization of the nature of these regulatory submissions regarding model details and intended applications. To address this gap, a landscape analysis of all the QSP submissions as of December 2020 was conducted. This report summarizes the (1) yearly trend of submissions, (2) proportion of submissions between INDs and NDAs/BLAs, (3) percentage distribution along the stages of drug development, (4) percentage distribution across various therapeutic areas, and (5) nature of QSP applications. In brief, QSP is increasingly applied to model and simulate both drug effectiveness and safety throughout the drug development process across disease areas., (Published 2021. This article is a U.S. Government work and is in the public domain in the USA. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objective: To compare analgesic efficacy, improvement in the quality of life, psychology and learning curve for iliopsoas (IP) injection using ultrasound (US) versus fluoroscopy (FL)., Methods: Thirty-six patients with chronic low back pain secondary to IP myofascial pain were randomly allocated into two groups and were given IP injection in prone position, using either FL or US as a guide. Pain scores were assessed using numerical rating scale (NRS); learning curve was evaluated by the number of attempts, time taken and subjective ease of performing the procedure. The psychological and quality of life assessment were done using Depression Anxiety Stress Scale (DASS) and Oswestry Disability Index (ODI), respectively., Results: FL and US guided IP injection had equianalgesic efficacy with a decrease in preprocedure NRS pain scores from mean value of 7.06 6 0.24 and 6.78 6 0.24, respectively, to 2.22 6 0.29 and 1.78 6 0.26 (at 24 hours), 1.50 6 0.22 and 1.50 6 0.23 (1 week), 0.50 6 0.12 and 0.56 6 0.15 (4 weeks) and 0.33 6 0.11 and 0.44 6 0.15 (12 weeks) (P < .001). The learning curve was easier for US intervention with average attempts of 1-2 compared to 1-3 for FL. The average time taken to perform IP intervention was lesser for US group. The improvement in DASS and ODI was comparable in both groups., Conclusion: FL and US both are effective modalities for IP muscle injection as they provide equal relief from pain, disability and psychological stress. US guided IP injections are easier to learn and perform in comparison with FL.

Selecting a dose regimen that is both safe and effective for patients is one of the most critical elements of a successful drug development program. Titrating the dose regimen of a drug based on patient response may help to identify safe and effective dosages at the individual patient level. Therefore, we quantified and characterized the use of response-guided titration for drugs recently approved by the US Food and Drug Administration (FDA) to assess how frequently this dosing strategy is used and how titration regimens are evaluated during drug development. Most of the 181 drugs approved from 2013-2017 (78%) had only one approved dosing regimen. Only 30 of 76 (39%) drugs that were considered amenable to response-guided dosing strategies had information in labeling about such strategies. These findings indicate that although response-guided titration can be found in labeling, this strategy is used in a minority of drugs for which it may be useful. Careful consideration should be made early in drug development as to whether a new drug is amenable to response-guided titration as an approach to reducing interpatient variability., (Published 2019. This article is a U.S. Government work and is in the public domain in the USA. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The recently enacted Prescription Drug User Fee Act (PDUFA) VI includes in its performance goals "enhancing regulatory science and expediting drug development." The key elements in "enhancing regulatory decision tools to support drug development and review" include "advancing model-informed drug development (MIDD)." This paper describes (i) the US Food and Drug Administration (FDA) Office of Clinical Pharmacology's continuing efforts in developing quantitative clinical pharmacology models (disease, drug, and clinical trial models) to advance MIDD, (ii) how emerging novel tools, such as organ-on-a-chip technologies or microphysiological systems, can provide new insights into physiology and disease mechanisms, biomarker identification and evaluation, and elucidation of mechanisms of adverse drug reactions, and (iii) how the single organ or linked organ microphysiological systems can provide critical system parameters for improved physiologically-based pharmacokinetic and pharmacodynamic evaluations. Continuous public-private partnerships are critical to advance this field and in the application of these new technologies in drug development and regulatory review., (Published 2019. This article is a U.S. Government work and is in the public domain in the USA. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Good practices around model-informed drug discovery and development (MID3) aim to improve the implementation, standardization, and acceptance of these approaches within drug development and regulatory review. A survey targeted to clinical pharmacology and pharmacometric colleagues across industry, the US Food and Drug Administration (FDA), and the European Medicines Agency (EMA) was conducted to understand current and future roles of MID3. The documented standards were generally affirmed as a "good match" to current industry practice and regulatory expectations, with some identified gaps that are discussed. All have seen at least a "modest" step forward in MID3 implementation associated with greater organizational awareness and share the expectation for a future wider use and impact. The priority within organizations was identified as a limitation with respect to the future of MID3. Finally, potential solutions, including a global overarching MID3 regulatory guideline, to facilitate greater acceptance by industry and regulatory decision makers are discussed., (© 2018 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Competing Interests: There are no conflicts of interest.

Our intent is to report a case of intercostal neuralgia occuring as a complication of splanchnic radiofreqency ablation (RFA), due to a breach in the integrity of the insulating sheath of the RFA needle.A 48-year-old man presented to our pain clinic with upper abdominal pain due to chronic pancreatitis, recalcitrant to medical management. We decided to perform bilateral splanchnic nerve RFA in this patient. After confirmation of bilateral correct needle placement under fluoroscopic guidance and sensorimotor testing, RFA was performed on the right side uneventfully. However, during RFA on the left side, the patient experienced severe pain in the epigastric region. A bolus of fentanyl 50 µg was given intravenously in order to minimise discomfort, and RFA was performed. In the post-procedure period, the patient described severe pain in the left subcostal and epigastric region, with features suggestive of intercostal neuralgia of the left 11th intercostal nerve. We went back and analysed all the fluoroscopic images again. Convinced of correct needle placement, we examined the RFA needles which had been used for ablation in this patient. One of the needles was discovered to have a fine breach in its insulating sheath, at a distance of approximately 30 mm from the active tip. It is of utmost importance for all interventional pain physicians to perform a thorough pre-use check of the equipment prior to any RFA procedure, with special emphasis on ensuring the integrity of the insulating sheath of the needles which are to be used, in order to prevent injury of non target nerves., Key Words: Splanchnic nerve block, radiofrequency ablation, intercostal neuralgia, radiofrequency ablation complications, radiofrequency equipment check, radiofrequency needle.

Background: Central neuraxial blockade (CNB) is an established technique of providing anesthesia for surgeries of the lower limb and abdomen. Hypotension is the most common side effect of CNB. It was hypothesized that by supplementing the initial burst of vasopressin following hypovolemia, hypotension following combined spinal epidural anesthesia (CSEA) could be avoided., Materials and Methods: A total of 122 patients undergoing lower limb and abdomen surgeries were included in the study, with 61 patients randomized into two groups - I and II. Patients in Group I received infusion of normal saline as soon as CSEA was applied. When systolic blood pressure (SBP) decreased to <90 mmHg, they received a 6 mg bolus of mephentermine to counteract hypotension. Patients in Group II received a continuous infusion of vasopressin as soon as CSEA was applied. If despite maximum dose of vasopressin, SBP dropped to < 90 mmHg, then intravenous mephentermine was administered to counteract hypotension. Hemodynamic parameters and side effects were noted., Results: Level of block attained in both groups was comparable in terms of dermatomal height. The mean SBP and mean arterial pressure values of Group I were significantly lower than in Group II in the initial 14 min. Diastolic BP was also significantly lower in Group I. Heart rate was found to be lower in Group II, especially after 30 min ( P < 0.05)., Conclusion: Maintaining plasma levels of the physiological burst of vasopressin helps to avoid hypotension following neuraxial blockade. Continuous infusion of vasopressin at 1-3 U/h can prevent hypotension following neuraxial blockade.

Aim: To compare retrocrural versus transaortic techniques for neurolytic celiac plexus block (NCPB) in patients suffering from upper abdominal malignancy., Methods: In this retrospective observational study between October 2013 and April 2015, 64 patients with inoperable upper abdominal malignancy received fluoroscopy-guided percutaneous NCPB in our institute. Their case files were reviewed and the patients were divided into two groups depending on the technique used to perform NCPB: retrocrural (Group R; n = 36) versus transaortic (Group T; n = 28). The primary outcome measure was pain as assessed with a numeric rating scale (NRS) from 0 to 10; the secondary outcome measures were morphine consumption per day (M), quality of life (QOL) as assessed by comparing the percent of positive responses in each group, and complications if any. These were noted and analyzed prior to intervention and then on day 1, weeks 1, 2, 3, and months 1, 2, 3, 6 following NCPB., Results: Patients in Group R had significantly reduced NRS pain scores at week 1, 2, 3, month 1 and 2 as compared to Group T (P < 0.05). Morphine consumption also reduced significantly in Group R at day 1, week 1, 2, and 3 (P < 0.05). QOL was found to be comparable between the groups, and no major complications were noted., Conclusion: Retrocrural NCPB provides superior pain relief along with a reduction in morphine consumption as compared to transaortic NCPB in patients with pain due to upper abdominal malignancy.

Over the past decade, personalized medicine has received considerable attention from researchers, drug developers, and regulatory agencies. Personalized medicine includes identifying patients most likely to benefit and those most likely to experience adverse reactions in response to a drug, and tailoring therapy based on pharmacokinetics or pharmacodynamic response, as well. Perhaps most exciting is finding ways to identify likely responders through genetic, proteomic, or other tests, so that only likely responders will be treated. However, less precise methods such as identifying historical, demographic, or other indicators of increased or reduced responsiveness are also important aspects of personalized medicine. The cardiovascular field has not used many genetic or proteomic markers, but has regularly used prognostic variables to identify likely responders. The development of biomarker-based approaches to personalized medicine in cardiovascular disease has been challenging, in part, because most cardiovascular therapies treat acquired syndromes, such as acute coronary syndrome and heart failure, which develop over many decades and represent the end result of several pathophysiological mechanisms. More precise disease classification and greater understanding of individual variations in disease pathology could drive the development of targeted therapeutics. Success in designing clinical trials for personalized medicine will require the selection of patient populations with attributes that can be targeted or that predict outcome, and the use of appropriate enrichment strategies once such attributes are identified. Here, we describe examples of personalized medicine in cardiovascular disease, discuss its impact on clinical trial design, and provide insight into the future of personalized cardiovascular medicine from a regulatory perspective., (© 2015 American Heart Association, Inc.)

Pain following thoracotomy is of moderate to severe nature. Management of thoracotomy pain is a challenging task. Post thoracotomy pain has acute effects in the post operative period by affecting respiratory mechanics, which increases the morbidity. Poorly controlled thoracotomy pain in the acute phase may also lead to the development of a chronic pain syndrome. A young male patient underwent esophagectomy and esophago-gastric anastomosis for corrosive stricture of the esophagus. Epidural analgesia is standard of care for patients undergoing thoracotomy. Due to hypotension and fluid losses following surgery, he was maintained on intravenous sedato-analgesia during postoperative mechanical ventilation. The thoracic epidural catheter which was placed pre-operatively, had developed blockage during the hospital stay. However, during weaning from ventilation and sedation, he indicated severe pain in the thoracotomy incision. The pain was severe enough to impair tidal breathing. We wanted to evaluate the efficacy of the serratus anterior plane block in the management of thoracotomy pain. The usefulness of this block has been discussed in the management of pain of rib fractures and breast surgeries. Despite the hypothesis of its usefulness in causing anaesthesia of the hemithorax, there are no available reports of clinical use for pain relief following thoracotomy. We performed the serratus anterior place block under ultrasound guidance and placed a catheter for continuous infusion of local anaesthetic and opioid. The patient had significant pain relief following a single bolus of the drug. The infusion was started thereafter, which provided excellent analgesia and facilitated an uneventful recovery. Here, we describe the successful management of thoracotomy pain using the serratus anterior plane block.

The effect of AKI and modern continuous RRT (CRRT) methods on drug disposition (pharmacokinetics) and response has been poorly studied. Pharmaceutical manufacturers have little incentive to perform pharmacokinetic studies in patients undergoing CRRT because such studies are neither recommended in existing US Food and Drug Administration (FDA) guidance documents nor required for new drug approval. Action is urgently needed to address the knowledge deficit. The Kidney Health Initiative has assembled a work group composed of clinicians and scientists representing academia, the FDA, and the pharmaceutical and dialysis industries with expertise related to pharmacokinetics, AKI, and/or CRRT. The work group critically evaluated key considerations in the assessment of pharmacokinetics and drug dosing in CRRT, practical constraints related to conducting pharmacokinetic studies in critically ill patients, and the generalizability of observations made in the context of specific CRRT prescriptions and specific patient populations in order to identify efficient study designs capable of addressing the knowledge deficit without impeding drug development. Considerations for the standardized assessment of pharmacokinetics and development of corresponding drug dosing recommendations in critically ill patients with AKI receiving CRRT are proposed., (Copyright © 2015 by the American Society of Nephrology.)

Purpose: To describe the U.S. Food and Drug Administration (FDA) review and approval of sorafenib (Nexavar; Bayer Pharmaceuticals Corp., Montville, NJ, and Onyx Pharmaceuticals Corp., Emeryville, CA), an oral kinase inhibitor, for the treatment of patients with unresectable hepatocellular carcinoma (HCC)., Experimental Design: The FDA independently analyzed an international, double-blind, placebo-controlled trial comparing the effect of best supportive care plus sorafenib or matching placebo on overall survival. Eligible patients had unresectable, biopsy-proven HCC and had not received prior systemic therapy., Results: Among the 602 randomized patients (placebo, 303; sorafenib, 299), baseline characteristics were well balanced, and 97% were Child-Pugh score A. HCC was "advanced" in 70% overall, as defined by extrahepatic metastases or by tumor radiographically visible in venous structures outside the liver. Underlying liver diseases included hepatitis B (18%), hepatitis C (28%), and alcohol-related (26%). The trial was stopped following a prespecified second interim analysis showing a statistically significant survival advantage for sorafenib [median, 10.7 vs 7.9 months; hazard ratio, 0.69 (95% confidence interval, (0.55, 0.87)), p = 0.00058]. Adverse events in sorafenib-treated patients included diarrhea in 55% (grade 3, 10%), hand-foot syndrome in 21% (grade 3, 8%), rash in 19% (grade 3, 1%), and cardiac ischemia or infarction in 2.7% (versus 1.3% for placebo). On sorafenib, treatment-emergent hypertension occurred in 9% of patients (placebo, 4%) and was grade 3 in 4% (placebo, 1%); elevated serum lipase occurred in 40% (placebo, 37%); hypophosphatemia occurred in 35% (placebo, 11%)., Conclusions: Sorafenib is the first systemic therapy to demonstrate a survival benefit in a randomized trial for unresectable HCC and has received FDA approval for this indication.