A call for transparent reporting to optimize the predictive value of preclinical research

The US National Institute of Neurological Disorders and Stroke convened major stakeholders in June 2012 to discuss how to improve the methodological reporting of animal studies in grant applications and publications. The main workshop recommendation is that at a minimum studies should report on sample-size estimation, whether and how animals were randomized, whether investigators were blind to the treatment, and the handling of data. We recognize that achieving a meaningful improvement in the quality of reporting will require a concerted effort by investigators, reviewers, funding agencies and journal editors. Requiring better reporting of animal studies will raise awareness of the importance of rigorous study design to accelerate scientific progress

Challenges in drug development for muscle disease: a stakeholders' meeting

Current treatment benefits for patients with muscle disease are limited, but progress in legislative and scientific initiatives have set the stage for the development of new therapies. The MD-CARE Act (Public Law 107-84), which allocates federal resources to muscular dystrophy, was approved by Congress and signed into law by the President of the United States in 2001. This has shifted the emphasis toward translational research. To facilitate a push toward therapy for muscle disorders, the Muscular Dystrophy Association (MDA) sponsored a meeting with representatives from industry, the Food and Drug Administration (FDA), the National Institutes of Health (NIH), and other government agencies and academia. Each contributed in different ways. The FDA helped define the necessary data to support investigational new drug (IND) applications including the design of proof-of-principle studies, outcome measures for clinical trials, and the pathway for developing surrogate measures for fast-tracking promising new drugs. The NIH, other government agencies, and the MDA described potential funding sources for translational research. Industry delineated a complementary role with academia, and academic investigators elucidated the current strengths and weaknesses of available clinical endpoints. The meeting provided a format for communication for diverse disciplines that usually have no common meeting ground, helping to lay the foundation for bringing products to market in a timely fashion

Gene therapy as a potential therapeutic option for Duchenne muscular dystrophy: A qualitative preference study of patients and parents.

ObjectivesDuchenne muscular dystrophy (DMD) is a rare neuromuscular disorder that causes progressive weakness and early death. Gene therapy is an area of new therapeutic development. This qualitative study explored factors influencing parents' and adult patients' preferences about gene therapy.MethodsWe report qualitative data from 17 parents of children with DMD and 6 adult patients. Participants responded to a hypothetical gene therapy vignette with features including non-curative stabilizing benefits to muscle, cardiac and pulmonary function; a treatment-related risk of death; and one-time dosing with time-limited benefit of 8-10 years. We used NVivo 11 to code responses and conduct thematic analyses.ResultsAll participants placed high value on benefits to skeletal muscle, cardiac, and pulmonary functioning, with the relative importance of cardiac and pulmonary function increasing with disease progression. More than half tolerated a hypothetical 1% risk of death when balanced against Duchenne progression and limited treatment options. Risk tolerance increased at later stages. Participants perceived a 'right time' to initiate gene therapy. Most preferred to wait until a highly-valued function was about to be lost.ConclusionParticipants demonstrated a complex weighing of potential benefits against harms and the inevitable decline of untreated Duchenne. Disease progression increased risk tolerance as participants perceived fewer treatment options and placed greater value on maintaining remaining function. In the context of a one-time treatment like gene therapy, our finding that preferences about timing of initiation are influenced by disease state suggest the importance of assessing 'lifetime' preferences across the full spectrum of disease progression

Supplementary Material - Supplement_S3 - The Rules of Engagement: CTTI Recommendations for Successful Collaborations Between Sponsors and Patient Groups Around Clinical Trials

<p>Supplementary Material - Supplement_S3 - The Rules of Engagement: CTTI Recommendations for Successful Collaborations Between Sponsors and Patient Groups Around Clinical Trials by Diane Bloom, Joel Beetsch, Matthew Harker, Sharon Hesterlee, Paulo Moreira, Bray Patrick-Lake, Wendy Selig, Jeffrey Sherman, Sophia K. Smith, James E.Valentine, and Jamie N. Roberts in Therapeutic Innovation & Regulatory Science</p

Supplementary Material - Supplement_S1 - The Rules of Engagement: CTTI Recommendations for Successful Collaborations Between Sponsors and Patient Groups Around Clinical Trials

<p>Supplementary Material - Supplement_S1 - The Rules of Engagement: CTTI Recommendations for Successful Collaborations Between Sponsors and Patient Groups Around Clinical Trials by Diane Bloom, Joel Beetsch, Matthew Harker, Sharon Hesterlee, Paulo Moreira, Bray Patrick-Lake, Wendy Selig, Jeffrey Sherman, Sophia K. Smith, James E.Valentine, and Jamie N. Roberts in Therapeutic Innovation & Regulatory Science</p

Supplementary Material - Supplement_S6 - The Rules of Engagement: CTTI Recommendations for Successful Collaborations Between Sponsors and Patient Groups Around Clinical Trials

<p>Supplementary Material - Supplement_S6 - The Rules of Engagement: CTTI Recommendations for Successful Collaborations Between Sponsors and Patient Groups Around Clinical Trials by Diane Bloom, Joel Beetsch, Matthew Harker, Sharon Hesterlee, Paulo Moreira, Bray Patrick-Lake, Wendy Selig, Jeffrey Sherman, Sophia K. Smith, James E.Valentine, and Jamie N. Roberts in Therapeutic Innovation & Regulatory Science</p

Supplementary Material - Supplement_S4 - The Rules of Engagement: CTTI Recommendations for Successful Collaborations Between Sponsors and Patient Groups Around Clinical Trials

<p>Supplementary Material - Supplement_S4 - The Rules of Engagement: CTTI Recommendations for Successful Collaborations Between Sponsors and Patient Groups Around Clinical Trials by Diane Bloom, Joel Beetsch, Matthew Harker, Sharon Hesterlee, Paulo Moreira, Bray Patrick-Lake, Wendy Selig, Jeffrey Sherman, Sophia K. Smith, James E.Valentine, and Jamie N. Roberts in Therapeutic Innovation & Regulatory Science</p

Whole-genome analysis of sporadic amyotrophic lateral sclerosis

Background: Approximately 90% of persons with amyotrophic lateral sclerosis (ALS) have the sporadic form, which may be caused by the interaction of multiple environmental factors and previously unknown genes. Methods: We performed a genomewide association analysis using 766,955 single-nucleotide polymorphisms (SNPs) found in 386 white patients with sporadic ALS and 542 neurologically normal white controls (the discovery series). Associations of SNPs with sporadic ALS were confirmed in two independent replication populations: replication series 1, with 766 case patients with the disease and 750 neurologically normal controls, and replication series 2, with 135 case patients and 275 controls. Results: We identified 10 genetic loci that are significantly associated (P\u3c0.05) with sporadic ALS in three independent series of case patients and controls and an additional 41 loci that had significant associations in two of the three series. The most significant association with disease in white case patients as compared with controls was found for a SNP near an uncharacterized gene known as FLJ10986 (P = 3.0 x 10-4; odds ratio for having the genotype in patients vs. controls, 1.35; 95% confidence interval, 1.13 to 1.62). The FLJ10986 protein was found to be expressed in the spinal cord and cerebrospinal fluid of patients and of controls. Specific SNPs seem to be associated with sex, age at onset, and site of onset of sporadic ALS. Conclusions: Variants of FLJ10986 may confer susceptibility to sporadic ALS. FLJ10986 and 50 other candidate loci warrant further investigation for their potential role in conferring susceptibility to the disease. Copyright © 2007 Massachusetts Medical Society

Whole-genome analysis of sporadic amyotrophic lateral sclerosis

Background: Approximately 90% of persons with amyotrophic lateral sclerosis (ALS) have the sporadic form, which may be caused by the interaction of multiple environmental factors and previously unknown genes. Methods: We performed a genomewide association analysis using 766,955 single-nucleotide polymorphisms (SNPs) found in 386 white patients with sporadic ALS and 542 neurologically normal white controls (the discovery series). Associations of SNPs with sporadic ALS were confirmed in two independent replication populations: replication series 1, with 766 case patients with the disease and 750 neurologically normal controls, and replication series 2, with 135 case patients and 275 controls. Results: We identified 10 genetic loci that are significantly associated (P\u3c0.05) with sporadic ALS in three independent series of case patients and controls and an additional 41 loci that had significant associations in two of the three series. The most significant association with disease in white case patients as compared with controls was found for a SNP near an uncharacterized gene known as FLJ10986 (P = 3.0 x 10-4; odds ratio for having the genotype in patients vs. controls, 1.35; 95% confidence interval, 1.13 to 1.62). The FLJ10986 protein was found to be expressed in the spinal cord and cerebrospinal fluid of patients and of controls. Specific SNPs seem to be associated with sex, age at onset, and site of onset of sporadic ALS. Conclusions: Variants of FLJ10986 may confer susceptibility to sporadic ALS. FLJ10986 and 50 other candidate loci warrant further investigation for their potential role in conferring susceptibility to the disease. Copyright © 2007 Massachusetts Medical Society