Faculty Bibliography

OBJECTIVE:To identify design elements of clinical trials leading to US Food and Drug Administration approval of drugs for neurological diseases with and without orphan indications. METHODS:We used publicly available information to identify approvals for drugs for neurological diseases with an orphan indication (n = 19) and compared them with recent approvals for drugs for neurological diseases without an orphan indication (n = 20). We identified "pivotal trials" from drug labels and drug approval packages, and assessed them on four elements of clinical trial design: control, blinding, randomization, and size. RESULTS:All drugs for neurological diseases (100%) approved without an orphan indication included at least two randomized, double-blind, placebo-controlled trials. In comparison, 32% of drugs with an orphan indication had at least two such trials (p < 0.001) and 74% had at least one (p = 0.02). Thirty-three pivotal trials were conducted for the 19 drugs approved with an orphan indication. Of the 33 trials, 11 (33%) did not use a placebo control, 9 (27%) were not double blind, and 4 (12%) were not randomized. Drugs approved without an orphan indication had more pivotal trials per drug (3.8 vs 1.7 trials; p < 0.001) and a larger mean trial size (506 vs 164 trial participants; p < 0.001). INTERPRETATION/CONCLUSIONS:The US Food and Drug Administration has approved orphan drugs for neurological diseases without randomized, doubled-blind, placebo-controlled pivotal trials. As orphan drug development grows, demand will likely increase for alternative designs for conducting adequate and well-controlled studies to demonstrate drug efficacy.

To achieve the goal of personalized medicine, advances in healthcare information technology (HIT) must be accompanied by similar advances in data analysis and translation into clinical care. For healthcare providers and their patients, advances in genomics and other related fields must be captured by sophisticated decision support systems that integrate information from multiple sources of data and facilitate their use in the clinic. In addition to addressing privacy concerns, regulators will also need to work toward establishing evidentiary standards for the use of data from electronic clinical sources in areas such as comparative effectiveness and safety, while addressing the complexity behind the genetic basis of the exceptions to their general findings. Overall, the increased use of HIT will allow for a more integrated, efficient system for collecting and analyzing clinical data, providing a fruitful environment for hypothesis testing and generation, as well as leading to more personalized and effective healthcare.

Organisms belonging to the genus Streptomyces produce numerous important secondary metabolites and undergo a sophisticated morphological differentiation program. In many instances these processes are under the control of gamma-butyrolactone (GBL) autoregulatory systems. Streptomyces acidiscabies strain 84.104 produces the secondary metabolite aromatic angucyclinone polyketide WS5995B. In order to explore the role of GBL regulatory circuitry in WS5995B production and morphogenesis in S. acidiscabies, a gene cluster encoding GBL autoregulatory signaling homologs was identified and characterized. Two GBL receptor homologs, sabR and sabS, were found flanking a GBL synthase homolog sabA. Strains carrying mutations in sabS produced elevated levels of WS5995B and displayed conditional morphological defects reminiscent of defects seen in Streptomyces bldA mutants. Notably, sabS possesses a TTA codon predicted to be recognized by tRNA(leu). sabA mutants produced higher levels of WS5995B than the wild-type strain but to a lesser extent than the levels of WS5995B seen in sabS mutants. Purified recombinant SabR and SabS were tested for their abilities to bind predicted AT-rich autoregulatory element (ARE) boxes within the sabRAS region. SabS did not bind any DNA sequences in this region, while SabR bound an ARE box in the region upstream of sabS. Quantitative reverse transcription-PCR analysis revealed higher levels of sabS transcript in sabR mutants than in the wild-type strain, suggesting that sabS expression is repressed by SabR. Based on these data, we propose that the S. acidiscabies sabRAS genes encode components of a signaling pathway which participates in the regulation of WS5995B production and morphogenesis.

Defendants who are accused of serious crimes sometimes feign amnesia to evade criminal responsibility. Previous research has suggested that feigning amnesia might impair subsequent recall. In two experiments, participants read and heard a story about a central character, described as "you," who was responsible for the death of either a puppy (Experiment 1) or a friend (Experiment 2). On free and cued recall tests immediately after the story, participants who had feigned amnesia recalled less than did participants who had recalled accurately. One week later, when all participants recalled accurately, participants who had previously feigned amnesia still performed worse than did participants who had recalled accurately both times. However, the participants who had formerly feigned amnesia did not perform worse than did a control group who had received only the delayed recall tests. Our results suggest that a "feigned amnesia effect" may reflect nothing more than differential practice at recall. Feigning amnesia for a crime need not impair memory for that crime when a person later seeks to remember accurately.

Recent reports describe hematopoietic abnormalities in mice with targeted instability of the mitochondrial genome. However, these abnormalities have not been fully described. We demonstrate that mutant animals develop an age-dependent, macrocytic anemia with abnormal erythroid maturation and megaloblastic changes, as well as profound defects in lymphopoiesis. Mice die of severe fatal anemia at 15 months of age. Bone-marrow transplantation studies demonstrate that these abnormalities are intrinsic to the hematopoietic compartment and dependent upon the age of donor hematopoietic stem cells. These abnormalities are phenotypically similar to those found in patients with refractory anemia, suggesting that, in some cases, the myelodysplastic syndromes are caused by abnormalities of mitochondrial function.