Review of the Food and Drug Administration's Center for Drug Evaluation and Research Program for New Molecular Entities: Trends and Regulatory Requirements in Mid-Cycle Communications.

The United States Food and Drug Administration (FDA) implemented "the Program" in 2012 to promote greater transparency and increased communication between the FDA and applicants of New Molecular Entity (NME) New Drug Applications (NDA) and original Biologics License Applications (BLA). We examined 128 publicly available NME NDA and original BLA approval packages reviewed and approved under the Program with the goal to educate regulatory professionals about the content and timing of communications from FDA to the Sponsor. This research found that the timing of communications between FDA and the Sponsor through the Mid-Cycle Communication (MCC) was consistent with the 21st-century Desk Reference Guide (DRG); 90% of internal FDA Mid-Cycle Meetings, MCCs with the applicant, and corresponding issuance of MCC minutes were within the target date. The content and format of the MCC were also consistent with the DRG and across disciplines. Almost all MCCs reviewed included a discussion on significant review issues, including major safety concerns. FDA's preliminary opinion on the necessity of a Risk Evaluation and Mitigation Strategy (REMS), which was predictive of REMS requirement at approval. The FDA's MCC comment on advisory committee meeting plans was highly predictive; if the MCC indicated an AC was planned, an AC meeting was held 91% of the time. With respect to the MCC, this research found the DRG and relevant FDA Manual of Policies and Procedures to be reliable resources to predict the FDA's planned actions associated with the review of a NME NDA or original BLA.

Review of the Food and Drug Administration's Center for Drug Evaluation and Research Program for New Molecular Entities: Trends and Regulatory Requirements in Acknowledgment Letters and Filing Communications.

The United States Food and Drug Administration (FDA) implemented the PDUFA V New Molecular Entity (NME) Program (the Program) in 2012 to promote greater transparency and increased communication between the FDA review team and applicants of NME New Drug Applications (NDA) and original Biologics License Applications (BLA). We reviewed 128 publicly available NME NDA and original BLA approval packages, submitted after October 2012 and approved by July 2018. Our research had a goal to educate regulatory professionals about the content and timing of communications from FDA to the Sponsor for approved drugs reviewed under the Program. This research found that communications issued within the first 74 days were consistent with the 21st Century Desk Reference Guide (DRG) targets; forecasted dates of other projected interactions included in the Filing Communication (FC) letter were often within 4 weeks of target. The content and format of the FC letter became more consistent with time, often including templated text. Approximately half the FC letters contained at least 1 filing review issue; however, not all appeared to be substantive. The FDA's preliminary comment on advisory committee meeting plans were predictive; 95% correlated with the need (or lack thereof) for an advisory committee meeting. Approximately 62% of FC letters contained actionable labeling comments, with nearly all related to editorial changes. With respect to the FC letter, this research found the DRG and relevant FDA Manual of Policies and Procedures to be reliable resources to predict the FDA's planned actions associated with the filing and review of a NME NDA or original BLA.

Design and evaluation of pyrazolopyrimidines as KCNQ channel modulators.

Effective treatments of neuropathic pain have been a focus of many discovery programs. KCNQ (kv7) are voltage gated potassium channel openers that have the potential for the treatment of CNS disorders including neuropathic pain. Clinical studies have suggested agents such as Retigabine to be a modulator of pain-like effects such as hyperalgesia and allodynia. In this paper, we describe the discovery and evaluation of a series of novel pyrazolopyrimidines and their affinity for potassium channels KCNQ2/3. These pyrazolopyrimidines have also shown good efficacy in the capsaicin-induced acute and secondary mechanical allodynia model and excellent pharmacokinetic properties, which may be superior to Retigabine.

Safety Profile of Baricitinib in Patients with Active Rheumatoid Arthritis with over 2 Years Median Time in Treatment.

OBJECTIVE: Baricitinib is an oral, once-daily selective Janus kinase (JAK1/JAK2) inhibitor for adults with moderately to severely active rheumatoid arthritis (RA). We evaluated baricitinib's safety profile through 288 weeks (up to September 1, 2016) with an integrated database [8 phase III/II/Ib trials, 1 longterm extension (LTE)]. METHODS: The "all-bari-RA" group included patients who received any baricitinib dose. Placebo comparison was based on the 6 studies with 4 mg and placebo up to Week 24 ("placebo-4 mg" dataset). Dose response assessment was based on 4 studies with 2 mg and 4 mg including LTE data ("2 mg-4 mg-extended"). The uncommon events description used the non-controlled all-bari-RA. RESULTS: There were 3492 patients who received baricitinib for 6637 total patient-years (PY) of exposure (median 2.1 yrs, maximum 5.5 yrs). No differences in rates of death, adverse events leading to drug discontinuation, malignancies, major adverse cardiovascular event (MACE), or serious infections were seen for 4 mg versus placebo or for 4 mg versus 2 mg. Infections including herpes zoster were significantly more frequent for 4 mg versus placebo. Deep vein thrombosis/pulmonary embolism were reported with 4 mg but not placebo [all-bari-RA incidence rate (IR) 0.5/100 PY]; the IR did not differ between doses (0.5 vs 0.6/100 PY, 2 mg vs 4 mg, respectively) or compared to published RA rates. All-bari-RA had 6 cases of lymphoma (IR 0.09/100 PY), 3 gastrointestinal perforations (0.05/100 PY), 10 cases of tuberculosis (all in endemic areas; 0.15/100 PY), and 22 all-cause deaths (0.33/100 PY). IR for malignancies (0.8/100 PY) and MACE (0.5/100 PY) were low and did not increase with prolonged exposure. CONCLUSION: In this integrated analysis of patients with moderate to severe active RA with exposure up to 5.5 years, baricitinib has an acceptable safety profile in the context of demonstrated efficacy. Trial registration numbers: NCT01185353, NCT00902486, NCT01469013, NCT01710358, NCT01721044, NCT01721057, NCT01711359, and NCT01885078 at clinicaltrials.gov.

The Effectiveness of Nurse Residency Programs on Retention: A Systematic Review.

New graduates account for the highest numbers of nurses entering and exiting the profession. Turnover is costly, especially in specialty settings. Nurse residency programs are used to retain new graduates and assist with their transition to nursing practice. The purpose of this systematic review of the literature was to examine new graduate nurse residency programs, residents' perceived satisfaction, and retention rates, and to make recommendations for implementation in perioperative settings. Results indicate increased retention rates for new graduates participating in residency programs and that residency participants experienced greater satisfaction with their orientation than those not participating in residency programs. Residency participants also perceived the residency as beneficial. Because residency programs vary in curricula and length, effectively comparing outcomes is difficult. More longitudinal data are needed. Data on residency programs specific to perioperative nursing are lacking. Considering the aging perioperative nursing workforce, residency programs could address critical needs for succession planning.

Postacute Care in Cancer Rehabilitation.

Acute care is usually associated with disease progression, treatments for cancer, and medical comorbidities. Patients with cancer may develop sudden functional deficits that require rehabilitation. Some of these patients benefit from acute rehabilitation, others benefit from subacute rehabilitation. After acute rehabilitation, continuous care for these patients has not been well described. Three studies are presented to demonstrate that cancer rehabilitation is a continuous process. Rehabilitation professionals should know how to detect fall risk, monitor symptoms, and render symptom management. Patients with cancer often require rehabilitation services during their entire disease trajectory.

The quality of Internet advertising in aesthetic surgery: an in-depth analysis.

BACKGROUND: The aesthetic market is a growing business, as evidenced by the American Society for Aesthetic Plastic Surgery (ASAPS) reporting an increase of 147% in the number of cosmetic procedures performed by members since 1997. This market is consumer-oriented, relying heavily on advertising for survival amid the increasing provider competition. OBJECTIVES: The authors evaluate trends, ethics, and efficacy of Internet advertising in aesthetic surgery. METHODS: Medical cosmetic providers in Southern California and their Web sites were catalogued through sales lists from manufacturers (Medicis and Allergan) and combined with advertised providers of surgical treatments. Using the ASAPS/American Society of Aesthetic Plastic Surgeons (ASPS) and American Medical Association Codes of Ethics as guidelines, scores were assigned to each Web site and evaluated with the provider's board certification. A geographical analysis determined whether the presence of high numbers of competitors had an impact on the adherence to ethical guidelines for advertising. To examine patient preferences in physician advertising, a survey was conducted online. RESULTS: Board-certified plastic surgeons showed the highest total ethical scores, followed by otolaryngologists, oromaxillofacial surgeons, and ophthalmologists. No decrement in the quality of the advertising was found in densely competitive environments. A consistent correlation was found between superior compliance with ethical guidelines and board certification in plastic surgery. The patient preference survey of 208 individuals demonstrated their desire for a well-trained, board-certified plastic surgeon to perform their cosmetic procedures. CONCLUSIONS: Although plastic surgeons demonstrate greater overall compliance with the ASAPS/ASPS Advertising Code of Ethics, they can continue to improve. With the large variety of cosmetic physicians offering the same procedures, maintaining open, honest, and forthright communication with the public is essential.

Who is providing aesthetic surgery? A detailed examination of the geographic distribution and training backgrounds of cosmetic practitioners in Southern California.

BACKGROUND: In recent years, there has been a significant increase in the number of non-plastic surgeons performing cosmetic procedures. This has the potential to have an impact on the plastic surgery practitioner by increasing competition and bringing into question the assurance of patient safety. In this study, a demographic analysis was performed of providers of invasive and minimally invasive cosmetic treatments in the Southern California region. METHODS: Providers of minimally invasive aesthetic procedures were catalogued using the sales lists from the manufacturers of the hyaluronic acid fillers Juvéderm and Restylane. The data set was further analyzed to enumerate the providers of surgical treatments, with a focus on the provision of liposuction. Data were analyzed using Environmental Systems Research Institute ArcGIS to focus on the Southern California area. Physician board certification and training background were detailed exhaustively. RESULTS: In the 45,238-square mile area encompassing the San Diego/Los Angeles megalopolis, there are 1867 cosmetic practitioners offering hyaluronic acid injections. Of this number, 495 are trained in plastic surgery. In the same geographic region, there are 834 individuals offering liposuction. Practitioners are concentrated in downtown Los Angeles and San Diego, where the potential patient-to-provider ratios are 1088:1 and 1185:1, respectively. Interestingly, primary care physicians comprise the third largest group providing hyaluronic acid fillers and the fourth largest group of liposuction providers. CONCLUSIONS: The authors' data demonstrate that there are numerous non-plastic surgeons performing cosmetic procedures, especially in the field of minimally invasive therapies. In addition, there is a growing contingent of non-surgery-trained individuals providing surgical cosmetic treatments, especially liposuction.

Rational design and synthesis of 4-((1R,2R)-2-hydroxycyclohexyl)-2(trifluoromethyl)benzonitrile (PF-998425), a novel, nonsteroidal androgen receptor antagonist devoid of phototoxicity for dermatological indications.

4-((1 R,2 R)-2-Hydroxycyclohexyl)-2(trifluoromethyl)benzonitrile [PF-0998425, (-)- 6a] is a novel, nonsteroidal androgen receptor antagonist for sebum control and treatment of androgenetic alopecia. It is potent, selective, and active in vivo. The compound is rapidly metabolized systemically, thereby reducing the risk of unwanted systemic side effects due to its primary pharmacology. (-)- 6a was tested negative in the 3T3 NRU assay, validating our rationale that reduction of conjugation might reduce potential phototoxicity.

Preparation of 4-aryl-2-trifluoromethylbenzonitrile derivatives as androgen receptor antagonists for topical suppression of sebum production.

A series of substituted 4-aryl-2-trifluoromethylbenzonitrile analogs were evaluated in the human androgen receptor binding and cellular functional assays. Analogs with sufficient in vitro binding and cellular potency (IC(50)<200 nM) were tested in the progesterone receptor binding assay for selectivity and in the Golden Syrian hamster ear model for in vivo efficacy. Within the series, compound 4 e was identified to be the most active analog in vivo (wax ester inhibition=86%).

Aminopyrrolidineamide inhibitors of site-1 protease.

The discovery and efficacy of a series of potent aminopyrrolidineamide-based inhibitors of sterol regulatory element binding protein site-1 protease is described.