A framework for assessing the impact of accelerated approval.

The FDA's Accelerated Approval program (AA) is a regulatory program to expedite availability of products to treat serious or life-threatening illnesses that lack effective treatment alternatives. Ideally, all of the many stakeholders such as patients, physicians, regulators, and health technology assessment [HTA] agencies that are affected by AA should benefit from it. In practice, however, there is intense debate over whether evidence supporting AA is sufficient to meet the needs of the stakeholders who collectively bring an approved product into routine clinical care.

The dinosaur from 600 BCE! Interpreting the dragon of Babylon, from archaeological excavation into fringe science.

In 1918, German archaeologist Robert Koldewey, excavator of Babylon, Iraq, observed that the depiction of the fantastical "dragon of Babylon" on the sixth century BCE Ishtar Gate must reference a real animal whose closest relatives would be dinosaurs like the iguanodon. Though ignored within archaeology, Koldewey's comments were taken up in German-American popular science writer Willy Ley's "romantic zoology" (1941), then by Bernard Heuvelmans (1955), founding figure in the fringe field of cryptozoology. Their interpretations would ultimately inspire expeditions by the International Society of Cryptozoologists in Central Africa to find the Mokele-Mbembe, a "living dinosaur," and migrate into Young Earth Creationist and ancient aliens theories.

Adaptive Designs: Results of 2016 Survey on Perception and Use.

Background: The DIA Adaptive Designs Scientific Working Group has a devoted subteam to performing surveys, literature reviews, and registry reviews every 4 years to assess the perception and use of adaptive designs (ADs) in the development of drugs and biologics.

Methods: A survey was distributed to pharmaceutical companies, academic institutions, and contract research organizations to collect information about the usage of ADs of different types and perception of challenges for their use. Literature and registry reviews were conducted to assess the prevalence of ADs of different types in drug and biologics development.

Secondary profunda femoris artery injury after intramedullary femoral nailing in a geriatric pertrochanteric femur fracture: case report.

We present a case of a secondary injury to the femoral artery in a geriatric male patient who sustained a pertrochanteric femoral fracture. Six days after closed fracture reduction and intramedullary femoral nailing, the patient presented with persistent hematocrit level drops, femoral swelling and pain. A computed tomography angiography of the femur revealed a perforation of the profunda femoris artery through the dislocated lesser trochanter fragment, and immediate surgical revision was induced.

Interleukin-13 associates with life-threatening rhinovirus infections in infants and young children.

Objective: Delineate risk factors associated with severe hypoxemia (O sat ≤87%) in infants and children younger than 2 years hospitalized with single pathogen HRV infection.

Study Design: Prospective study in a yearly catchment population of 56 560 children <2 years old between 2011 and 2013 in Argentina. All children with respiratory signs and O sat <93% on admission were included.

Ethical Considerations in Adaptive Design Clinical Trials.

Adaptive design clinical trial methodologies offer both opportunities and challenges for observing basic ethical principles in human subject research. Using both published and unpublished adaptive design clinical trials, we have selected and reviewed examples of clinical trials with different design adaptations to discuss the ethical obstacles presented and often successfully resolved by these approaches, including (1) confirmatory trials for treatments widely accepted on the basis of uncontrolled case series or open-label trials (clinical equipoise and "justice" in the sense of which trial groups will "receive the benefits of research and bear its burdens") (infantile hemangioma/propranolol); (2) interim results analysis by unblinded data monitoring committees ("withholding information necessary to make a considered judgment" ["respect for persons"] versus compromising the trial's scientific basis) (BIG 1-98); (3) adaptations involving sample size reassessment or dose adjustment via dropping or adding treatment arms, allowing fewer subjects to produce statistically significant results, fewer subjects treated with ineffective/toxic doses, and more subjects given doses showing tolerance and treatment activity ("beneficence" or "protecting from harm and making efforts to secure wellbeing") (ECMO, Neuromyelitis Optica); (4) adaptive randomization inferential problems balanced against ethical benefits (trastuzumab vs taxane in advanced gastric cancer; ADVENT); (5) more efficient allocation of societal resources for research, in both public and commercial realms, versus uncertain regulatory acceptance (indicaterol; VALOR); and (6) platform, umbrella, and basket trials offering additional efficiencies (I-SPY II, BATTLE, Lung-MAP). The importance of careful design, meticulous planning, and rigorous ethical review of adaptive design trials on a case-by-case basis cannot be overemphasized.

DIA's Adaptive Design Scientific Working Group (ADSWG): Best Practices Case Studies for "Less Well-understood" Adaptive Designs.

Adaptive design (AD) clinical trials use accumulating subject data to modify the parameters of the design of an ongoing study, without compromising the validity and integrity of the study. The 2010 US Food and Drug Administration (FDA) Draft Guidance on Adaptive Design Clinical Trials described a subset of 7 primary design types as "less well-understood." FDA defined these designs as those with limited regulatory experience.

Addressing Challenges and Opportunities of "Less Well-Understood" Adaptive Designs.

The draft adaptive design guidance released by FDA in 2010 included references to adaptive study designs that were described as "less well-understood." At that time, there was relatively little regulatory experience with such designs, and their properties were felt to be insufficiently understood. In order to promote greater use of adaptive designs, especially those categorized as less well-understood, the Best Practice Subteam of the DIA Adaptive Designs Scientific Working Group (ADSWG) has worked on describing and characterizing these designs, identifying challenges associated with them and suggesting improvements to design or study conduct aspects that might make them more acceptable.

Respiratory Severity Score Separates Upper Versus Lower Respiratory Tract Infections and Predicts Measures of Disease Severity.

A respiratory severity score (RSS) describing acute respiratory illness (ARI) severity would be useful for research and clinical purposes. A total of 630 term infants presenting with ARI had their RSS measured. RSS was higher in those with lower respiratory tract infection (LRTI) compared with those with upper respiratory infection (URI; LRTI 6.

Examining breast cancer screening barriers among Central American and Mexican immigrant women: fatalistic beliefs or structural factors?

Researchers have examined "cancer fatalism" (the belief that cancer is predetermined, beyond individual control, and necessarily fatal) as a major barrier to breast cancer screening among Latinas. The authors examine perceptions of breast cancer, its causes, and experiences with screening among Salvadoran, Guatemalan, Mexican, and Bolivian immigrant women in Washington, DC. Two salient themes emerged: (a) perceptions of breast cancer causes and breast cancer screening; and (b) structural factors are the real barriers to breast cancer screening.

Views on Emerging Issues Pertaining to Data Monitoring Committees for Adaptive Trials.

In this paper, the authors express their views on a range of topics related to data monitoring committees (DMCs) for adaptive trials that have emerged recently. The topics pertain to DMC roles and responsibilities, membership, training, and communication. DMCs have been monitoring trials using the group sequential design (GSD) for over 30 years.

Induced, selective proteolysis of MLK3 negatively regulates MLK3/JNK signalling.

MLK3 (mixed lineage kinase 3) is a MAP3K [MAPK (mitogen-activated protein kinase) kinase kinase] that activates multiple MAPK pathways, including the JNK (c-Jun N-terminal kinase) pathway. Immunoblotting of lysates from cells ectopically expressing active MLK3 revealed an additional immunoreactive band corresponding to a CTF (C-terminal fragment) of MLK3. In the present paper we provide evidence that MLK3 undergoes proteolysis to generate a stable CTF in response to different stimuli, including PMA and TNFalpha (tumour necrosis factor alpha).