Considerations for Industry-Preparing for the FDA Model-Informed Drug Development (MIDD) Paired Meeting Program.

A recent industry perspective published in this journal describes the benefits received by drug companies from participation in the MIDD Pilot Program. Along with the primary objectives of supporting good decision-making in drug development, there were substantial savings in time and development costs. Furthermore, many sponsors reported qualitative benefits such as new learnings and clarity on MIDD strategies and methodology that could be applied to other development programs. Based on the success of the Pilot Program, the FDA recently announced the continuation of the MIDD Paired Meeting Program as part of the Prescription Drug User Fee Act (PDUFA VII). In this report, we describe the collective experiences of industry participants in the MIDD Program to date, including all aspects of the process from meeting request submission to follow-up actions. The purpose is to provide future participants with information to optimize the value of the MIDD Program.

Clinical Pharmacology of Brigatinib: A Next-Generation Anaplastic Lymphoma Kinase Inhibitor.

Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor designed to overcome mechanisms of resistance associated with crizotinib, is approved for the treatment of ALK-positive advanced or metastatic non-small cell lung cancer. After oral administration of single doses of brigatinib 30-240 mg, the median time to reach maximum plasma concentration ranged from 1 to 4 h. In patients with advanced malignancies, brigatinib showed dose linearity over the dose range of 60-240 mg once daily. A high-fat meal had no clinically meaningful effect on systemic exposures of brigatinib (area under the plasma concentration-time curve); thus, brigatinib can be administered with or without food. In a population pharmacokinetic analysis, a three-compartment pharmacokinetic model with transit absorption compartments was found to adequately describe brigatinib pharmacokinetics. In addition, the population pharmacokinetic analyses showed that no dose adjustment is required based on body weight, age, race, sex, total bilirubin (< 1.5× upper limit of normal), and mild-to-moderate renal impairment. Data from dedicated phase I trials have indicated that no dose adjustment is required for patients with mild or moderate hepatic impairment, while a dose reduction of approximately 40% (e.g., from 180 to 120 mg) is recommended for patients with severe hepatic impairment, and a reduction of approximately 50% (e.g., from 180 to 90 mg) is recommended when administering brigatinib to patients with severe renal impairment. Brigatinib is primarily metabolized by cytochrome P450 (CYP) 3A, and results of clinical drug-drug interaction studies and physiologically based pharmacokinetic analyses have demonstrated that coadministration of strong or moderate CYP3A inhibitors or inducers with brigatinib should be avoided. If coadministration with a strong or moderate CYP3A inhibitor cannot be avoided, the dose of brigatinib should be reduced by approximately 50% (strong CYP3A inhibitor) or approximately 40% (moderate CYP3A inhibitor), respectively. Brigatinib is a weak inducer of CYP3A in vivo; data from a phase I drug-drug interaction study showed that coadministration of brigatinib 180 mg once daily reduced the oral midazolam area under the plasma concentration-time curve from time zero to infinity by approximately 26%. Brigatinib did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations in vitro. Exposure-response analyses based on data from the ALTA (ALK in Lung Cancer Trial of AP26113) and ALTA-1L pivotal trials of brigatinib confirm the favorable benefit versus risk profile of the approved titration dosing regimen of 180 mg once daily (after a 7-day lead-in at 90 mg once daily).

A Systematic Review and Meta-Analysis Comparing the Clinical Outcomes of Profunda Artery Perforator Versus Gracilis Thigh Flap as a Second Choice for Autologous Breast Reconstruction.

PURPOSE: Autologous breast reconstruction remains a versatile option to produce a natural appearing breast after mastectomy. The deep inferior epigastric perforator remains the most commonly used flap choice, but when this donor site is unsuitable or unavailable, the transverse upper gracilis (TUG) or profunda artery perforator (PAP) flaps are popular secondary alternatives. We conduct a meta-analysis to better understand patient outcomes and adverse events in secondary flap selection in breast reconstruction. METHODS: A systematic search was conducted on MEDLINE and Embase for all articles published on TUG and/or PAP flaps for oncological breast reconstruction in postmastectomy patients. A proportional meta-analysis was conducted to statistically compare outcomes between PAP and TUG flaps. RESULTS: The TUG and PAP flaps were noted to have similar reported rates of success and incidences of hematoma, flap loss, and flap healing (P > 0.05). The TUG flap was noted to have significantly more vascular complications (venous thrombosis, venous congestion, and arterial thrombosis) than the PAP flap (5.0% vs 0.6%, P < 0.01) and significantly greater rates of unplanned reoperations in the acute postoperative period (4.4% vs 1.8%, P = 0.04). Infection, seroma, fat necrosis, donor healing complications, and rates of additional procedures all exhibited high degree of heterogeneity precluding mathematical synthesis of outcomes across studies. CONCLUSIONS: Compared with TUG flaps, PAP flaps have fewer vascular complications and fewer unplanned reoperations in the acute postoperative period. There is need for greater homogeneity in reported outcomes between studies to enable for synthesis of other variables important in determining flap success.

Therapeutic Development in Polyarticular Course Juvenile Idiopathic Arthritis: Extrapolation, Dose Selection, and Clinical Trial Design.

OBJECTIVE: Stakeholders met to address persistent challenges facing the development of therapeutics for polyarticular juvenile idiopathic arthritis (pJIA), which result in fewer approved therapies for children with pJIA than adults with rheumatoid arthritis (RA) and long lag times from adult RA approval to pediatric labeling. Ensuring that new medications are authorized in a timely manner to meet the needs of JIA patients worldwide is critically important to multiple stakeholders. METHODS: The Food and Drug Administration in collaboration with the University of Maryland Center for Regulatory Science and Innovation held a public workshop entitled "Accelerating Drug Development for pJIA" on October 2, 2019, to address challenges surrounding access to new medications for children and adolescents with pJIA. Regulatory, academic, and industry stakeholders, as well as patient representatives, participated in the workshop, which consisted of 4 sessions, including panel discussions. RESULTS: The workshop facilitated broad public discussion of challenges facing the development of pJIA therapeutics, highlighting areas of need and outlining opportunities to expedite development, while underscoring the necessity of close collaboration between all stakeholders, including patients and families. CONCLUSION: This report summarizes key aspects of the workshop, including the appropriate application of innovative approaches to the development of pJIA therapeutics, including extrapolation, to address current challenges and provide timely access to newer safe and effective treatments. Long-term safety assessment is of pressing concern to stakeholders and cannot be fully extrapolated from adult studies but requires consistent postmarketing long-term follow-up.

Trapeziectomy versus joint replacement for first carpometacarpal (CMC 1) joint osteoarthritis: a systematic review and meta-analysis.

PURPOSE: This systematic review and meta-analysis directly compares joint replacement (JR) and trapeziectomy techniques to provide an update as to which surgical intervention is superior for first carpometacarpal (CMC-1) joint osteoarthritis. METHODS: In August 2020, MEDLINE, Embase and Web of Science were searched for eligible studies that compared these two techniques for the treatment of CMC-1 joint osteoarthritis (PROSPERO registration ID: CRD42020189728). Primary outcomes included the Disabilities of the Arm, Shoulder and Hand (DASH), QuickDASH (QDASH) and pain visual analogue scale (VAS) scores. Secondary outcomes, such as total complication, dislocation and revision surgery rates, were also measured. RESULTS: From 1909 studies identified, 14 studies (1005 patients) were eligible. Our meta-analysis found that post-operative QDASH scores were lower for patients in the JR group (five studies, p = 0.0004). Similarly, significantly better postoperative key pinch strength in favour of JR was noted (three studies, p = 0.001). However, pain (VAS) scores were similar between the two groups (five studies, p = 0.21). Moreover, JR techniques had significantly greater odds of overall complications (12 studies; OR 2.12; 95% CI 1.13-3.96, p = 0.02) and significantly greater odds of revision surgery (9 studies; OR 5.14; 95% CI 2.06-12.81, p = 0.0004). CONCLUSION: Overall, based on very low- to moderate-quality evidence, JR treatments may result in better function with less disability with comparable pain (VAS) scores; however, JR has greater odds of complications and greater odds of requiring revision surgery. More robust RCTs that compare JR and TRAP with standardised outcome measures and long-term follow-up would add to the overall quality of evidence.

A Disease Progression Model to Quantify the Nonmotor Symptoms of Parkinson's Disease in Participants With Leucine-Rich Repeat Kinase 2 Mutation.

Leucine-rich repeat kinase 2 (LRRK2) inhibitors are currently in clinical development as interventions to slow progression of Parkinson's disease (PD). Understanding the rate of progression in PD as measured by both motor and nonmotor features is particularly important in assessing the potential therapeutic effect of LRRK2 inhibitors in clinical development. Using standardized data from the Critical Path for Parkinson's Unified Clinical Database, we quantified the rate of progression of the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I (nonmotor aspects of experiences of daily living) in 158 participants with PD who were carriers and 598 participants with PD who were noncarriers of at least one of three different LRRK2 gene mutations (G2019S, R1441C/G, or R1628P). Age and disease duration were found to predict baseline disease severity, while presence of at least one of these three LRRK2 mutations was a predictor of the rate of MDS-UPDRS Part I progression. The estimated progression rate in MDS-UPDRS Part I was 0.648 (95% confidence interval: 0.544, 0.739) points per year in noncarriers of a LRRK2 mutation and 0.259 (95% confidence interval: 0.217, 0.295) points per year in carriers of a LRRK2 mutation. This analysis demonstrates that the rate of progression based on MDS-UPDRS Part I is ~ 60% lower in carriers as compared with noncarriers of LRRK2 gene mutations.

An elevated C-reactive protein level in an inpatient rehabilitation setting after joint replacement: To act or not to act? - that is the question.

ABSTRACT: C-reactive protein (CRP) is part of a battery of "routine bloods" performed by residents on patients when they are admitted into a rehabilitation unit. Generally, an elevated CRP is considered to be an indicator of an acute infective process. Numerous studies have indicated that the CRP peaks on the 2nd or 3rd day post total hip arthroplasty (THR) and total knee arthroplasty (TKR) and returns to normal by day 7. When the CRP level remains elevated, it is generally felt that infection should be excluded.We performed a prospective study on 45 consecutive patients admitted into a rehabilitation unit post hip and knee arthroplasty over a 6 months period, to evaluate the incidence of an elevated CRP on admission, to determine whether an isolated elevated CRP on admission to a rehabilitation setting should not be considered as an indicator of an infective process.We found all patients (100%) had elevated CRP's on admission, ranging from 8.6 mg/L to 139.2 mg/L, between days 5-7 post-operatively. By day 14, CRP's reduced, but 91% of patients still had elevated CRP's, ranging from 2.1 mg/L to 47.3 mg/L after THR and 4.8 mg/L to 40 mg/L after TKR at day 14.These results suggest that even in uncomplicated elective joint arthroplasty, CRP's can remain elevated up to 14 days post-procedure, in the absence of an infective process.An isolated elevated CRP on admission to a rehabilitation setting should not be considered as an indicator of an infective process, but rather part of the normal post-operative inflammatory response. The elevated CRP should be monitored and only an upward trend requires further investigation and management.

Pivotal Dose of Pembrolizumab: A Dose-Finding Strategy for Immuno-Oncology.

Despite numerous publications emphasizing the value of dose finding, drug development in oncology is dominated by the mindset that higher dose provides higher efficacy. Examples of dose finding implemented by biopharmaceutical firms can change this mindset. The purpose of this article is to outline a pragmatic dose selection strategy for immuno-oncology (IO) and other targeted monoclonal antibodies (mAbs). The approach was implemented for pembrolizumab. Selecting a recommended phase II dose (RP2D) with a novel mechanism of action is often challenging due to uncertain relationships between pharmacodynamics measurements and clinical end points. Additionally, phase I efficacy and safety data are generally inadequate for RP2D selection for IO mAbs. Here, the RP2D was estimated based on phase I (clinical study KN001 A and A2) pharmacokinetics data as the dose required for target saturation, which represents a surrogate for maximal pharmacological effect for antagonist mAbs. Due to limitations associated with collecting and analyzing tumor biopsies, characterizing intratumoral target engagement (TE) is challenging. To overcome this gap, a physiologically-based pharmacokinetic model was implemented to predict intratumoral TE. As tumors are spatially heterogeneous, TE was predicted in well-vascularized and poorly vascularized tumor regions. Additionally, impact of differences in target expression, for example, due to interindividual variability and cancer type, was simulated. Simulations showed that 200 mg every 3 weeks can achieve ≥ 90% TE in clinically relevant scenarios, resulting in the recommendation of 200 mg every 3 weeks as the RP2D. Randomized dose comparison studies (KN001 B2 and D) showing similar efficacy over a fivefold dose/exposure range confirmed the RP2D as the pivotal dose.

The Role of Virtual Consultations in Plastic Surgery During COVID-19 Lockdown.

BACKGROUND: COVID-19 has led to government enforced 'lockdown' in the UK severely limiting face-to-face patient interaction. Virtual consultations present a means for continued patient access to health care. Our aim was to evaluate the use of virtual consultations (VCons) during lockdown and their possible role in the future. METHODS: An anonymous survey was disseminated to UK and European plastic surgeons via social media, email sharing and via the European Association of Societies of Aesthetic Plastic Surgery newsletter. Uptake of VCons, modality, effectiveness, safety and future utility were assessed. RESULTS: Forty-three senior plastic surgeons responded to the survey. The majority of the respondents (97.7%) reported using VCons during COVID-19 lockdown, of which 74.4% had no prior experience. Two-thirds of surgeons utilised commercial platforms such as Zoom, FaceTime and Skype, 38.1% of respondents did not know about or were unsure about adequate encryption for health care use, and just under a half (47.6%) reported they were unaware of or lacking GDPR compliance. Most (97.6%) say they are likely to use virtual consultations after lockdown. CONCLUSION: Virtual consultations have had a crucial role in patient care during UK lockdown. It is clear that they will serve as an adjunct to face-to-face consultation in the future. Further regulation is required to ensure platforms offer adequate safety and security measures and are compliant with relevant data protection laws. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Collaborations between Clinical Pharmacologists in Japan and in the United States - Report from the IQ CPLG and JPMA CPTF Meeting in Tokyo, Japan.

The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) Clinical Pharmacology Leadership Group (CPLG) held its first meeting of Japan-based representatives at Astellas Pharma headquarters in Tokyo on October 1, 2019. The meeting was also attended by Japan Pharmaceutical Manufactures Association (JPMA) Clinical Pharmacology Task Force (CPTF) members. Overall, nearly 30 clinical pharmacologists representing 14 companies attended the event. The meeting met its goal of enhancing mutual understanding of each organization's activities. In a number of break-out sessions, participants identified scientific topics for potential future collaboration between JPMA CPTF and IQ CPLG.

The quality of online information regarding non-surgical aesthetic procedures.

BACKGROUND: The rapid growth of non-surgical aesthetics has led to a scarcity of regulation that raises concerns for serious consequences to public health. Services are advertised primarily through websites which are not necessarily centrally monitored or maintained to a set gold standard. We quantitatively assess the quality of online information regarding non-surgical procedures in order to promote patient safety and informed decision making. METHODS: Google and Bing, search engines that represent 95.27of global searches, were queried with the expanded search terms "facial filler" and "Botox". The top 100 results were sampled and two validated tools were used to assess the quality of healthcare information retrieved; the DISCERN instrument and the JAMA benchmark criteria. RESULTS: Once duplicates were removed, a total of 77 unique websites were retrieved by the search. The majority of websites were published by private marketing firms. The median score for website quality across all included websites was 'fair' (42) when assessed according to the DISCERN instrument, and 'poor' (1) when assessed against the JAMA criteria. Private websites had the lowest quality of information online and institutional websites had the highest. CONCLUSION: Non-surgical aesthetics are becoming increasingly popular with patients and clinicians due to their convenience, scope of treatment, and novel and strategic marketing. Online information available to patients, however, is often of poor quality, dominated by private clinics and commercial entities, and thus presents a significant risk of misinforming patients desiring to undertake these procedures. Significant reform and regulation of information is required in order to make this industry safer for patients.

A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation.

BACKGROUND: Pembrolizumab is approved for multiple cancer types at 200 mg and 2 mg/kg dose every 3 weeks (Q3W). We used a model-based approach to compare the exposure of pembrolizumab 400 mg dose every 6 weeks (Q6W) with the Q3W regimens. METHODS: The Q6W dose was selected by matching exposure with the 200 mg and 2 mg/kg Q3W doses. Concentration-time profiles were simulated using the established population pharmacokinetic model of pembrolizumab based on 2993 subjects from five clinical trials across tumour types. Efficacy was bridged by evaluating projections of average concentration over the dosing interval (Cavg) and trough concentration (Cmin) at steady state (ss). Safety was bridged by ensuring that concentrations were below those at 10 mg/kg dose every 2 weeks (Q2W), the maximum clinical dose. RESULTS: The 400 mg Q6W dose had similar predicted exposure (Cavg,ss, geometric mean âˆ¼1% higher) as the 200 mg Q3W dose. Fewer than 1% of subjects had transiently lower Cmin,ss than that observed for 200 mg and 2 mg/kg Q3W. Despite these reductions, similar target saturation is expected. The predicted peak concentrations (Cmax,ss) for 400 mg Q6W were substantially (∼65%) lower than the 10 mg/kg Q2W dose. CONCLUSIONS: Exposures expected for pembrolizumab 400 mg Q6W were similar to the 200 mg and 2 mg/kg Q3W and below the 10 mg/kg Q2W regimens. Established exposure-response relationships for pembrolizumab over a 5-fold dose range (2 mg/kg Q3W to 10 mg Q2W) support that clinical efficacy and safety of 400 mg Q6W would be similar to the 200 mg and 2 mg/kg Q3W doses across tumour types. CLINICAL TRIAL REGISTRATION NUMBERS: NCT01295827, NCT01704287, NCT01866319, NCT01905657, NCT02142738.