Clinical Trials Review

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Solving the Drug Pipeline Problem through Improving the Clinical Trial Process

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Abstract
Each year fewer drugs are being approved by the FDA, yet the pharmaceutical industry is spending astronomical amounts developing new compounds. Modifications in the clinical trial process are needed in order to encourage the development of new possible therapeutics and bring new drugs onto the market. Reviewing the necessity of animal modeling, the institution of phase 0 and adaptive trial designs, improvement in patient recruitment, and collaboration between industry and academia are suggested as possible solutions to improve the number of compounds entering clinical trials. This review paper will discuss the successes and drawbacks of these solutions. Introduction

In the past decade, drug development has significantly decreased as fewer new drugs are arriving to market despite increased research and development spending. In 2010, despite only 15 new molecular entities were approved by the FDA compared to 53 in 1996, 39 in 1997, and 30 in 19981. The increasing expenses of developing new drugs as well as stricter approval standards by the FDA is deterring companies from creating new medicines2. Therefore changes to the clinical trial process are needed make them more flexible, economical, and quicker to prevent the further decline in development of drugs. Current method of Clinical trails

The modern clinical trial consists of six stages. These are in vitro studies, phase 0(first in man), 1 (safety and toxicity), 2(efficacy), 3(compared to current treatment), and 4 (post approval). In vitro studies need to be carried out on two animal models, the most common being mice however other animals can be used ranging from worms to zebra fish3. These animal models are used to evaluate absorption, distribution, metabolism, excretion and toxicity of compound before testing in humans3. If appropriate the compound in small doses (approximately one tenth of therapeutic dose) can be tested in phase 0 to obtain preclinical data in healthy humans or patients, often between 10-15 subjects12. Pharmacokinetic and pharmacodynamics data are gathered however if small enough doses are given than they may not be able to be assayed limiting phase 0 data. After phase 0, phase 1 trials are conducted in small groups (<100) of healthy humans to monitor safety and again pharmacokinetics and pharmacodynamics6. Then phase 2 trials are undertaken in larger groups (<300) to determine efficacy and toxic effects6. Large patient groups are recruited in phase 3 trials randomized to receive the new therapy either with or in comparison to the current therapy6. After the drugs passes the phase 3 trial and is reviewed by the FDA, it receives a notice of compliance (NOC) and can be put on the market. Phase 4 is often called post marketing monitoring as it occurs after release to ensure safety and efficacy of drug. The current clinical trial process alone takes over ten years, about 802 million dollars per drug, and is highly failure prone as 80% of drugs fail between phase 3 and market3. Hence modifications are needed to the clinical trial process to reduce time and spending on compounds while encouraging more compounds to be taken to clinical testing. Animal Models

Animal models have been successful in modeling disease progressions, through identifying the drug targets and revealing adverse drug reactions before the drug is further developed however focus has been mainly on selectivity and efficacy4. This focus causes many compounds to be excluded from clinical trials as it is not financially feasible to pursue these leads that are non-selective or have low efficacy further. Scientists need to be more open-minded and understand the strengths and limitations when using animal models to simulate human conditions. Furthermore considerations in results need to be given to the differences between humans and animals in anatomy, histology, physiology and...
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