Averting Clinical Trial Drug Failure Through Preclinical Studies

Clinical Research Process Advances in Research The Common Fund programs of the National Institutes of Health (NIH) include the PROMIS (Patient-Reported Outcomes Measurement Information System) initiative (NIH, 2013). The PROMIS initiative seeks to exploit the creative potential of researchers and clinicians, for the purpose of developing new methods for reporting patient outcomes; however, in contrast to more quantitative measures, such as laboratory tests and radiological findings, the PROMIS initiative is focused on outcomes from the perspective of patients.

These outcomes can include patient reports of changes in pain levels, activities of daily living, cognitive performance, social connectedness, and psychological health. These outcome measures will be used to inform researchers and clinicians about an intervention's effectiveness, from a relevant and potentially more meaningful perspective. Passage of the 2010 Patient Protection and Affordable Care Act provided funds for the creation of the Patient-Centered Outcomes Research Institute (PCORI), a non-profit institute dedicated to improving the quality and relevance of the evidence used for making evidence-based healthcare decisions (PCORI, 2014).

Recently, PCORI announced funding for 46 new research projects, totaling $102 million, for clinical effectiveness research (CER) projects (PR Newswire, 2014). This amount is on top of the $671 million in awards that have been made since PCORI began funding research projects in 2012. The main focus of the most recent funding decision is patient-centered outcomes in obesity and patient transitions from hospital to home.

The Addressing Disparities Program will award two $10 million dollar grants for studying obesity treatments offered in the primary care setting, while the Healthcare Systems Program will award almost $15 million to help identify services that benefit patients the most when transitioning from hospital to home. In addition, eight awards incorporating the goals of the PROMIS initiative have been made available. Patient-centered outcomes-focused research is also being funded by the National Cancer Institute (NCI).

Researchers funded by the NCI recently examined quality of life (QOL) outcomes in patients' comorbid with gynecologic cancer and obesity (Doll et al., 2014). An earlier study had revealed a negative relationship between BMI and QOL; therefore, a relatively large sample of patients (N = 152) were interviewed over the phone using the Functional Assessment of Cancer Therapy-General Population (FACT-GP) and the PROMIS global mental health and global physical health (GPH) instruments. Obesity was common among the patients, with 65% having a BMI ? 30 kg/m2.

Among the many possible confounding variables tested, only age and cancer site were significant predictors of QOL. The independent variable BMI was also a significant predictor of social QOL (p = .05) using the FACT-GP instrument, although physical (p = .07) and emotional (p = .09) QOL were trending towards significance. The GPH instrument revealed BMI was a significant predictor of patient-reports of physical health (p = .01) and a non-significant predictor of patient-reports of mental health (p = .06). Adjusting for age, insurance status, and cancer site did not alter the GPH findings.

The study by Doll and colleagues (2014) was only the second to be published that examined the relationship between QOL and BMI in patients with gynecologic cancers. When combined, a relatively minor number of patients (N = 185) have been studied to date. The announcement of an additional $102 million in awards to study patient-centered outcomes, especially concerning obesity, should help increase the amount and quality of scientific evidence showing a relationship between obesity and QOL.

Per the goals of the PROMIS initiative, the findings of Doll and colleagues (2014) revealed that patients suffering from gynecologic cancer and obesity report significantly worse physical and mental quality of life. These findings correlate with the data generated by the FACT-GP survey instrument, findings valuable for helping clinicians and researchers improve the clinical effectiveness of medical interventions. Preclinical Development As Glasser (2007) notes, Big Pharma has suffered repeatedly after promising new drugs turned out to have safety and efficacy shortcomings in clinical trials.

The resulting injury to patients and loss of untold millions in research and development dollars has been fuel for reimagining the optimal bench to bedside pipeline. Currently, the drug pipeline takes anywhere from 5 to 12 years and can cost $800 million dollars with no assurance of success. If researchers could develop preclinical methods that would minimize the safety and efficacy risks associated with novel drugs, earlier in the pipeline, both patients and Big Pharma would benefit.

Of primary concern, according to Glaser (2007), are bioavailability, pharmacokinetics, and toxicity; although, the latter is widely considered the primary reason for drug failures after pharmacokinetics was shifted to earlier stages of the drug development process. Among the preclinical technologies receiving attention is Absorption, Distribution, Metabolism, and Excretion Toxicity (ADME-Tox) assays (Glaser, 2007). Absorption is similar to bioavailability because it is concerned with the ability of an orally-administered drug to cross the intestinal epithelium (Guttendorf, 2011). Cell and tissue culture techniques have been developed to facilitate absorption studies of a candidate drug.

The value of in vitro absorption findings are limited, however, by the extent to which a drug can be utilized once it has crossed into the circulatory system. Although valuable insights concerning a drug's absorption activity can be gleamed from a careful analysis of chemical structure, in vitro cell culture assays remain essential. An analysis of chemical structure can also be informative regarding a drug's metabolic profile, however, the use of hepatocyte cultures remain the preferred tool.

Cultured hepatocytes and hepatic tissue slices retain many of the enzymatic activities that would be observed in vivo, thereby providing valuable insights into a drug's metabolic profile. Among those techniques gaining both industry and regulatory acceptance is the hERG (human Ether-a-go-go-Related Gene) assay, because this gene produces a potassium channel known to be involved in long QT syndrome and sudden cardiac arrest (Glaser, 2007). Any interaction with the potassium channel would probably be considered fatal to a drug's development.

The general experimental approach across all these techniques is to test the toxicity of a candidate drug using multiple cell lines, while measuring multiple variables. The.