Analytical approaches to reporting long-term clinical trial data.

BACKGROUND AND SCOPE: Long-term clinical studies are essential for monitoring the effectiveness and safety of a drug. Information provided by long-term clinical studies complements the results of short-term, randomized, controlled trials, which often form the basis of regulatory approval for a new drug application. As the duration of a study increases and the number of patients continuing in the study declines, missing data become more of a problem: they may bias the results. Therefore, standard analytical strategies used in short-term randomized, controlled trials (intent-to-treat, per-protocol) may not always be appropriate for data generated in long-term studies. OBJECTIVE: To review commonly used analytical approaches in the assessment of clinical trial data and to identify and address issues related to these approaches in the analysis of long-term study data. FINDINGS: The authors suggest the use of an intent-to-observe population in long-term studies, applying at least three different analytical methods for handling missing data, testing for bias as a sensitivity analysis and reporting results of more than one method if they differ from one another. LIMITATIONS: Statistical approaches to data analysis are not addressed in this review. CONCLUSION: The use of multiple analyses is supported by regulatory authority and expert guidelines, although it has not been widely adopted in the medical literature. Given the inherent limitations of accounting for missing data with each method, the multiple-analysis approach provides more information with which to make better informed decisions, and clearly defined multiple analytical methods may prevent misleading conclusions from being drawn.

The loss of circadian PAR bZip transcription factors results in epilepsy.

DBP (albumin D-site-binding protein), HLF (hepatic leukemia factor), and TEF (thyrotroph embryonic factor) are the three members of the PAR bZip (proline and acidic amino acid-rich basic leucine zipper) transcription factor family. All three of these transcriptional regulatory proteins accumulate with robust circadian rhythms in tissues with high amplitudes of clock gene expression, such as the suprachiasmatic nucleus (SCN) and the liver. However, they are expressed at nearly invariable levels in most brain regions, in which clock gene expression only cycles with low amplitude. Here we show that mice deficient for all three PAR bZip proteins are highly susceptible to generalized spontaneous and audiogenic epilepsies that frequently are lethal. Transcriptome profiling revealed pyridoxal kinase (Pdxk) as a target gene of PAR bZip proteins in both liver and brain. Pyridoxal kinase converts vitamin B6 derivatives into pyridoxal phosphate (PLP), the coenzyme of many enzymes involved in amino acid and neurotransmitter metabolism. PAR bZip-deficient mice show decreased brain levels of PLP, serotonin, and dopamine, and such changes have previously been reported to cause epilepsies in other systems. Hence, the expression of some clock-controlled genes, such as Pdxk, may have to remain within narrow limits in the brain. This could explain why the circadian oscillator has evolved to generate only low-amplitude cycles in most brain regions.