The US Food and Drug Administration’s expedited approval programs: addressing premarket flexibility with enhanced postmarket evidence generation

When the editors of Clinical Trials solicited our review on the U.S. Food and Drug Administration’s (FDA) expedited development and review programs, we anticipated there would be accompanying commentaries from other academics with differing opinions, or perhaps from the perspectives of industry or venture capital. We hardly expected to initiate a discussion among the former Commissioner of the FDA, the current Director of the Center for Drug Evaluation and Research (CDER), and the Chief Medical Officer of the American Society of Clinical Oncology on the advantages and disadvantages to patients and clinicians of FDA’s expedited approval programs. But we appreciate the opportunity to have done so. To be clear, the goal of our review was to engage in constructive dialogue, discussing the implications of expedited approval programs on premarket and postmarket evidence generation, highlighting some specific concerns, and offering our recommendations for robust medical product evaluations that ensure high-quality clinical evidence is available to inform patient care and clinical decision-making. The FDA faces the challenging task of striking the right balance between ensuring that novel therapeutics are safe and effective and allowing promising new drugs to enter the market as quickly as possible. We agree with Dr. Califf that FDA’s regulatory approach should not ‘revert back to the strategy of the 1970s’.2 Likely in response to the desires frequently expressed by patients and clinicians, the U.S. Congress has enacted laws requiring the FDA to develop expedited development and review pathways to accelerate the availability of novel therapeutics. Some of these pathways necessarily offer potential flexibility with respect to the evidentiary standards that are required to demonstrate medical product safety and effectiveness and secure approval. Accordingly, we believe there is a need for corresponding efforts to strengthen the clinical evidence that is generated after market approval

The US Food and Drug Administration’s expedited approval programs: Evidentiary standards, regulatory trade-offs, and potential improvements

The United States Food and Drug Administration (FDA) has several regulatory programs and pathways to expedite the development and approval of therapeutic agents aimed at treating serious or life-debilitating conditions. A common feature of these programs is the regulatory flexibility, which allows for a customized approval approach that enables market authorization on the basis of less rigorous evidence, in exchange for requiring postmarket evidence generation. An increasing share of drugs approved by the FDA in recent years are associated with expedited programs. In this paper, we provide an overview of the evidentiary standards required by FDA’s expedited development and approval programs, summarize the findings of the recent academic literature demonstrating some of the limitations of these programs, and outline potential opportunities to address these limitations. Recent evidence suggests that therapeutic agents in the FDA’s expedited programs are approved on the basis of fewer and smaller studies that may lack comparator groups and random allocation, and rather than focusing on clinical outcomes for study endpoints, rely instead on surrogate markers of disease. Once on the market, agents receiving expedited approvals are often quickly incorporated into clinical practice and evidence generated in the postmarketing period may not necessarily address the evidentiary limitations at the time of market entry. Furthermore, not all pathways require additional postmarketing studies. Evidence suggests that drugs in expedited approval programs are associated with a greater likelihood that FDA will take a safety action following market entry. There are several opportunities to improve the timeliness, information value, and validity of the pre-and postapproval studies of drugs receiving expedited approvals. When use of nonrandomized and uncontrolled studies cannot be avoided prior to market entry, randomized trials should be mandatory in the postapproval period, unless there are strong justifications for not carrying out such studies. In the premarket period, validity of the surrogate markers can be improved by more rigorously evaluating their correlation with patient-relevant clinical outcomes. Opportunities to reduce the duration, complexity, and cost of postmarketing randomized trials should not compromise their validity and instead incorporate pragmatic ‘real-world’ design elements. Despite recent enthusiasm for widely using real world evidence, adaptive designs, and pragmatic trials in the regulatory setting, caution is warranted until large scale empirical evaluations demonstrate their validity compared to more traditional trial design

Somatosensory attention identifies both overt and covert awareness in disorders of consciousness

Objective Some patients diagnosed with disorders of consciousness retain sensory and cognitive abilities beyond those apparent from their overt behavior. Characterizing these covert abilities is crucial for diagnosis, prognosis, and medical ethics. This multimodal study investigates the relationship between electroencephalographic evidence for perceptual/cognitive preservation and both overt and covert markers of awareness. Methods Fourteen patients with severe brain injuries were evaluated with an electroencephalographic vibrotactile attention task designed to identify a hierarchy of residual somatosensory and cognitive abilities: (1) somatosensory steady-state evoked responses, (2) bottom-up attention orienting (P3a event-related potential), and (3) top-down attention (P3b event-related potential). Each patient was also assessed with a clinical behavioral scale and 2 functional magnetic resonance imaging assessments of covert command following. Results Six patients produced only sensory responses, with no evidence of cognitive event-related potentials. A further 8 patients demonstrated reliable bottom-up attention-orienting responses (P3a). No patient showed evidence of top-down attention (P3b). Only those patients who followed commands, whether overtly with behavior or covertly with functional neuroimaging, also demonstrated event-related potential evidence of attentional orienting. Interpretation Somatosensory attention-orienting event-related potentials differentiated patients who could follow commands from those who could not. Crucially, this differentiation was irrespective of whether command following was evident through overt external behavior, or through covert functional neuroimaging methods. Bedside electroencephalographic methods may corroborate more expensive and challenging methods such as functional neuroimaging, and thereby assist in the accurate diagnosis of awareness

The Consequences and Costs of Maternal Substance Abuse in New York City

We use a pooled time-series cross-section of live births in New York City between 1980 and 1989 to investigate the dramatic rise in low birthweight, especially among Blacks, that occurred in the mid 1980s. After controlling for other risk factors, we estimate that the number of excess low birthweight births attributable to illicit substance abuse over this period ranged from approximately 1,900 to 3,800 resulting in excess neonatal admission costs of between $22 and$53 million. We conclude that illicit substance use was a major contributory factor in rapid rise of low birthweight among Blacks in New York City in the latter part of the 1980s. The impact of prenatal illicit substance use on Whites and Hispanics is less conclusive.

Assessing awareness in severe Alzheimer’s disease

There is an urgent need to understand the nature of awareness in people with severe Alzheimer’s disease (AD) to ensure effective person-centered care. Objective biomarkers of awareness validated in other clinical groups (e.g., anesthesia, minimally conscious states) offer an opportunity to investigate awareness in people with severe AD. In this article we demonstrate the feasibility of using Transcranial magnetic stimulation (TMS) combined with EEG, event related potentials (ERPs) and fMRI to assess awareness in severe AD. TMS-EEG was performed in six healthy older controls and three people with severe AD. The perturbational complexity index (PCIST) was calculated as a measure of capacity for conscious awareness. People with severe AD demonstrated a PCIST around or below the threshold for consciousness, suggesting reduced capacity for consciousness. ERPs were recorded during a visual perception paradigm. In response to viewing faces, two patients with severe AD provisionally demonstrated similar visual awareness negativity to healthy controls. Using a validated fMRI movie-viewing task, independent component analysis in two healthy controls and one patient with severe AD revealed activation in auditory, visual and fronto-parietal networks. Activation patterns in fronto-parietal networks did not significantly correlate between the patient and controls, suggesting potential differences in conscious awareness and engagement with the movie. Although methodological issues remain, these results demonstrate the feasibility of using objective measures of awareness in severe AD. We raise a number of challenges and research questions that should be addressed using these biomarkers of awareness in future studies to improve understanding and care for people with severe AD

An assessment of the methodological quality of published network meta-analyses: a systematic review

Objective To assess the methodological quality of published network meta-analysis. Design Systematic review. Methods We searched the medical literature for network meta-analyses of pharmaceuticals. We assessed general study characteristics, study transparency and reproducibility, methodological approach, and reporting of findings. We compared studies published in journals with lower impact factors with those published in journals with higher impact factors, studies published prior to January 1st, 2013 with those published after that date, and studies supported financially by industry with those supported by non-profit institutions or that received no support. Results The systematic literature search identified 854 citations. Three hundred and eighteen studies met our inclusion criteria. The number of network meta-analyses has grown rapidly, with 48% of studies published since January 2013. The majority of network meta-analyses were supported by a non-profit institution or received no support (68%). We found considerable inconsistencies among reviewed studies. Eighty percent reported search terms, 61% a network diagram, 65% sufficient data to replicate the analysis, and 90% the characteristics of included trials. Seventy percent performed a risk of bias assessment of included trials, 40% an assessment of model fit, and 56% a sensitivity analysis. Among studies with a closed loop, 69% examined the consistency of direct and indirect evidence. Sixty-four percent of studies presented the full matrix of head-to-head treatment comparisons. For Bayesian studies, 41% reported the probability that each treatment was best, 31% reported treatment ranking, and 16% included the model code or referenced publicly-available code. Network meta-analyses published in higher impact factors journals and those that did not receive industry support performed better across the assessment criteria. We found few differences between older and newer studies. Conclusions There is substantial variation in the network meta-analysis literature. Consensus among guidelines is needed improve the methodological quality, transparency, and consistency of study conduct and reporting

Use of polyethylene glycol coatings for optical fibre humidity sensing

Humidity induced change in the refractive index and thickness of the polyethylene glycol (PEG) coatings are in situ investigated for a range from 10 to 95%, using an optical waveguide spectroscopic technique. It is experimentally demonstrated that, upon humidity change, the optical and swelling characteristics of the PEG coatings can be employed to build a plastic fibre optic humidity sensor. The sensing mechanism is based on the humidity induced change in the refractive index of the PEG film, which is directly coated onto a polished segment of a plastic optical fibre with dip-coating method. It is observed that PEG, which is a highly hydrophilic material, shows no monotonic linear response to humidity but gives different characteristics for various ranges of humidity levels both in index of refraction and in thickness. It undergoes a physical phase change from a semi-crystal line structure to a gel one at around 80% relative humidity. At this phase change point, a drastic decrease occurs in the index of refraction as well as a drastic increase in the swelling of the PEG film. In addition, PEG coatings are hydrogenated in a vacuum chamber. It is observed that the hydrogen has a preventing effect on the humidity induced phase change in PEG coatings. Finally, the possibility of using PEG coatings in construction of a real plastic fibre optic humidity sensor is discussed. (C) 2008 The Optical Society of Japan

Consciousness-specific dynamic interactions of brain integration and functional diversity

Abstract: Prominent theories of consciousness emphasise different aspects of neurobiology, such as the integration and diversity of information processing within the brain. Here, we combine graph theory and dynamic functional connectivity to compare resting-state functional MRI data from awake volunteers, propofol-anaesthetised volunteers, and patients with disorders of consciousness, in order to identify consciousness-specific patterns of brain function. We demonstrate that cortical networks are especially affected by loss of consciousness during temporal states of high integration, exhibiting reduced functional diversity and compromised informational capacity, whereas thalamo-cortical functional disconnections emerge during states of higher segregation. Spatially, posterior regions of the brain’s default mode network exhibit reductions in both functional diversity and integration with the rest of the brain during unconsciousness. These results show that human consciousness relies on spatio-temporal interactions between brain integration and functional diversity, whose breakdown may represent a generalisable biomarker of loss of consciousness, with potential relevance for clinical practice

Ga0.35In0.65 N0.02As0.08/GaAs bidirectional light-emitting and light-absorbing heterojunction operating at 1.3 μm

The Top-Hat hot electron light emission and lasing in semiconductor heterostructure (HELLISH)-vertical-cavity semiconductor optical amplifier (THH-VCSOA) is a bidirectional light-emitting and light-absorbing heterojunction device. The device contains 11 Ga0.35In0.65 N0.02As0.08/GaAs MQWs in its intrinsic active region which is enclosed between six pairs of AlAs/GaAs top distributed Bragg reflectors (DBRs) and 20.5 pairs of AlAs/GaAs bottom DBR mirrors. The THH-VCSOA is fabricated using a four-contact configuration. The wavelength conversion with amplification is achieved by the appropriate biasing of the absorption and emission regions within the device. Absorption and emission regions may be reversed by changing the polarity of the applied voltage. Emission wavelength is about 1,300 nm and a maximum gain at this wavelength is around 5 dB at T = 300 K

Safety and Efficacy of the FRED Jr Flow Re-Direction Endoluminal Device for Intracranial Aneurysms: Retrospective Multicenter Experience With Emphasis on Midterm Results

Background and Purpose: Flow diversion is increasingly used as an endovascular treatment for intracranial aneurysms. In this retrospective multicenter study, we analyzed the safety and efficacy of the treatment of intracranial, unruptured, or previously treated but recanalized aneurysms using Flow Re-Direction Endoluminal Device (FRED) Jr with emphasis on midterm results. Materials and Methods: Clinical and radiological records of 150 patients harboring 159 aneurysms treated with FRED Jr at six centers between October 2014 and February 2020 were reviewed and consecutively included. Clinical outcome was measured by using the modified Rankin Scale (mRS). Anatomical results were assessed according to the O’Kelly-Marotta (OKM) scale and the Cekirge-Saatci Classification (CSC) scale. Results: The overall complication rate was 24/159 (16%). Thrombotic-ischemic events occurred in 18/159 treatments (11%). These resulted in long-term neurological sequelae in two patients (1%) with worsening from pre-treatment mRS 0–2 and mRS 4 after treatment. Complete or near-complete occlusion of the treated aneurysm according to the OKM scale was reached in 54% (85/158) at 6-month, in 68% (90/133) at 1-year, and in 83% (77/93) at 2-year follow-up, respectively. The rates of narrowing or occlusion of a vessel branch originating from the treated aneurysm according to the CSC scale were 11% (12/108) at 6-month, 20% (17/87) at 1-year, and 23% (13/57) at 2-year follow-up, respectively, with all cases being asymptomatic. Conclusions: In this retrospective multicenter study, FRED Jr was safe and effective in the midterm occlusion of cerebral aneurysms. Most importantly, it was associated with a high rate of good clinical outcome