History phase trials

The development of nucleic acid-based therapeutics is not as straightforward as researchers had initially anticipated. Stability, toxicity, specificity, and delivery of the compounds continue to be challenging issues that need further optimization. In recent years, researchers have come up with intricate solutions that have greatly improved the efficacy of potential antisense, ribozyme, as well as RNAi-based therapeutics. Clinical trials for all these types of nucleic acid-based therapeutics are underway. So far, data from several trials and studies in animal models look promising, in particular, the therapies that trigger the RNAi pathway. However, history has shown that compounds that do well in phase I or phase II clinical trials may still fail in phase III. A striking example is the nonspecific suppression of angiogenesis by siRNA via toII-Iike receptor 3 (Kleinman et al. 2008). It will become clear in the near future which compounds will make it as a new class of antiviral therapeutics. 

NRTls are structural analogues of the natural nucleotides that form the building blocks of RNA and DNA in human cells. Their use as part of HAART has dramatically modified the natural history of HIV infection. They, however, cause a range of drag- or tissue-specific toxicides zidovudine (AZT) causes myopathy zalcitabine (ddC), didanosine (ddl), and lamivudine (3TC) cause neuropathy stavudine (d4T) causes neuropathy or myopathy and lactic acidosis (Dalakas 2001). During phase 1 and 11 trials, the dose-limiting toxicity of didanosine, zalcitabine, and stavudine was identified as peripheral neuropathy (Dalakas 2001). 

But even large phase III trials are rarely designed as natural history trials. The latter require closely following thousands of patients, often... 

Initial clinical work focused on a product that would be used to convert patients who were hospitalized for recent-onset AF as an alternative to a cardioversion procedure. Cardiome partnered with Fujisawa (now Astellas Pharmaceuticals) for the clinical development of a vernakalant (1), which produces robust AF conversion rates and none of the ventricular conduction abnormalities associated with less selective agents.35 By the close of 2009, vernakalant had been in 5 large trials and several smaller trials, including a total of over 1200 AF patients. Four Phase III studies—Atrial Arrhythmia Conversion Trials (ACT 1, 2, 3, and 4) —examined patients with recent onset AF (< 45 days) and the measured the rate of conversion to NSR in various periods after drug administration.36 38 The conversion rate was 45-63% in these studies, which tended to exclude patients with more compromised heart function or a history of heart failure. While there has been no specific study looking at QT prolongation, monitoring in both patients and in healthy volunteers showed only modest increases in the QT interval with no directly associated incidents of TDP across all trials. 

The history of supramolecular carbene chemistry is not long. Preliminary trials, during the 1970s, involved the generation of carbenes in the presence of micelles, e.g., quaternary ammonium salts, and crown ethers.72 However, carbene host ICs were not formed, nor were they sought. Instead, these hosts enable phase transfer catalysis (PTC) of Lewis acid-Lewis base reactions, e.g., the SN2 reaction (Equation (1)). 

For example, first-in-man studies and pivotal trials are more likely to be audited than phase IV trials, and external providers selected for the first time who are responsible for key areas in clinical trials should be audited with a higher priority than CROs with a long history and reliable performance. 

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