Clinical studies/trials safety issues

Many of the safety issues concerning naked pDNA are similar to those of conventional pharmaceutical agents, such as the inherent toxicity of the pDNA itself. However, the use of pDNA for the delivery of therapeutic proteins poses novel theoretical safety concerns. These concerns involve any toxicity associated with expression of the encoded protein, the potential for unexpected and untoward consequences as a result of the persistent expression of a therapeutic protein which could lead to autoimmune disease, the biodistribution of the pDNA, and the potential for a transformation event resulting from the integration of the pDNA into chromosomal DNA. The safety of naked pDNA has now been well documented in pre-clinical studies in animals, and more recently, in clinical trials in humans. 

Before a drug may be tested on humans, it must first be tested on animals. Tests on humans are called clinical trials, and animal trials are often referred to as preclinical trials. Preclinical trials differ from the animal tests mentioned earlier in this chapter. The previously discussed animal tests help the drug discovery team determine and optimize the pharmacodynamic and pharmacokinetic behavior of a hit or lead. Preclinical trials, in contrast, are standardized, industrywide tests. The preclinical tests have technical names such as Segment II Reproductive Study in Rabbits or 6-Month Toxicity Study in Rats. The specific names suggest the exact nature of each study. Each trial seeks to answer predefined safety questions concerning a drug candidate. Preclinical trials do not address the therapeutic effectiveness of the drug candidate in any way. Preclinical trials examine exclusively safety issues. 

Nonclinical Studies In vitro (laboratory) or in vivo (animal) pharmacology, toxicology and pharmacokinetic studies that support the testing of a product in humans. Usually at least two species are evaluated prior to Phase I clinical trials. Nonclinical studies continue throughout all phases of research to evaluate long-term safety issues. 

In cases where a relevant species has not been identified, a multifaceted approach may be taken. This was the case for S. typhi, a human-restricted strain vaccine, which used a combination of in vitro and in vivo studies and a weight of evidence approach. Also, by changing the formulation to include hog mucin and the route of administration from subcutaneous to intraperitoneal, the mouse, which was previously not sensitive, became sensitive to the pathogen, which enabled levels of attenuation to be assessed. The vaccine entered into a phase I clinical trial with no reported safety issues.27... 

Clinical trial monitoring includes those activities that ensure that the study is being conducted according to the protocol. Monitoring permits an in-process assessment of the quality of the data being collected. The first alert to safety issues is often revealed during the process of monitoring the clinical trial. 

In summary, the findings of early Phase I and II clinical trials suggest subjective and objective improvements in patients with ischemic lower-extremity or myocardial disease, and merit further investigation in additional Phase II, and pivotal Phase III and IV clinical studies. Issues that need to be addressed in these studies include limitations and safety profiles, definition of the populations that would benefit from this therapy, determination of... 

Most centers or offices have access to a wide network of inspectors. These inspectors operate worldwide, and audit both animal and clinical studies, as well as manufacturing processes and premises. Such audits can be for cause , e.g. a complaint from the public or an emergent safety issue, or routine . Pivotal clinical trials in a submitted NDA or BLA will usually garner an inspection of the clinical trials sites and statutory documentation. 

---