International Journal of Clinical Practice Assignment

Assignment Task

1. Introduction

Developers of drugs biologicals, and medical devices must ensure product safety demonstrate medical benefit in people and mass produce the product. Preclinical development starts before clinical trials and the main goal are to determine the safety and effectiveness of the intervention. Research may include pharmacodynamics pharmacokinetics absorption distribution metabolism and excretion studies and toxicity testing. During preclinical studies in vitro and in vivo testing is performed. Toxicity includes studies of which organs are targeted and long-term carcinogenic effects or effects on mammalian reproduction. Two species of animals are normally used in drug development studies. Choice is determined on which animal gives the best correlation to human studies. Medical devices are usually studied in larger animal species. No Observed Adverse Effect Level (NOAEL), the level of exposure at which there is no biologically or statistically significant increase in the frequency or severity of any adverse effects in the exposed population when compared to its appropriate control, is established based on preclinical trials. These are used to determine initial Phase I clinical trial dosage levels on a mass active pharmaceutical ingredient (API) per mass patient basis. If preclinical studies show that the therapy is safe and effective, clinical trials, defined as “scientifically controlled studies of the safety and effectiveness of a therapeutic agent using consenting human subjects”, are started. The four possible outcomes are: 1) the new treatment has a large beneficial effect and is superior to standard treatment; 2) the new treatment is equivalent to standard treatment; 3) the new treatment is neither clearly superior nor clearly inferior to standard treatment; or 4) a new treatment is inferior to standard treatment. The US Food and Drug Administration (FDA) role begins after preclinical evaluation for safety and effectiveness.

These prospective studies are designed to answer specific questions about biomedical or behavioral interventions and must adhere to the principles of good clinical practices (GCP) [1]-[5]. Classification of the trial may reflect how the researchers behave (observational versus interventional clinical trials), by their purpose (prevention, screening, diagnostic, treatment, quality of life, or expanded access clinical trials), or whether the trial design allows changes based on data accumulated during the trial (fixed versus adaptive clinical trials). Ten areas that are carefully assessed in these clinical studies are protection of human subjects, sampling, degree of masking, randomization, intention to treat analysis, selection of interventional and comparison groups, selection of end points, interpretation of results, trial duration, and selection of traditional versus equivalence testing. Randomized controlled trials (RCT) are the gold standard and are often used to evaluate the efficacy or effectiveness of various types of medical intervention and may provide information about adverse effects [6]-[10]. Classifications of RCT’s include study design (parallel-group, crossover, cluster, or factorial), outcome of interest (efficacy versus effectiveness), and evaluation of a hypothesis (superiority, noninferiority, or equivalence) [11] [12]. The people being studied are randomly allocated to one of the different treatments that are under study. The ideal randomization process maximizes statistical power, minimizes selection bias, and minimizes allocation bias.

Phase Clinical Trials

The National Institutes of Health (NIH) announced a series of initiatives to address the growing crisis in moving new basic science discoveries to the market where they are available for patient use. One of the objectives was strengthening clinical research infrastructure [21]. This was followed by an FDA report issued in March 2004 analyzing the “Challenge and Opportunity on the Critical Path to New Medical Products” [22]. US Pharmaceutical R & D Spending and the NIH Budget had increased dramatically

1. A Phase I clinical trial evaluates the best way to administer a drug, its frequency and dose, the maximum tolerated dose (MTD), and side effects. Tolerability, pharmacokinetics, and pharmacodynamics are evaluated. These studies determine, most importantly, if the treatment is safe. Trials usually include 20 to 100 patients and are monitored by the clinical researcher. Doses are increased if there are no severe side effects and patients are tested to determine if he or she is responding to the therapy. These escalation dose studies are used to determine the best and safest dose that can be administered and is a fraction of the dose that caused harm during animal testing. Unnecessary exposure of subjects to subtherapeutic doses while maintaining safety and rapid accrual is the primary goal of Phase I trials [29]. Subjects, in most cases, are healthy volunteers although patients with a certain disease may be required. Contract research organizations usually conduct these studies and stipends may be given. Testing is usually sequential with data being reviewed after every patient or small group of patients.

2. Phase I/II dose finding studies determine the most successful dose (MSD) which is the dose which maximizes the product of the probability of seeing no toxicity together with the probability of seeing a therapeutic response. While a Phase I clinical study focuses on determining the MTD, Phase II studies evaluate potential efficacy and characterizes treatment benefit for the disease in a convincing manner. The intervention is not presumed to have any therapeutic effect whatsoever. These studies are performed on larger groups (100 to 300 subjects) and are designed to assess how well the drug works and to continue safety assessments. Therapeutic doses which were determined during Phase I are administered and patients are monitored by the clinical researcher. Trials are often conducted in a multi-institution setting. Phase II may be divided into Phase IIA which are pilot clinical trials to evaluate efficacy and safety in selected populations with the disease or condition to be treated, diagnosed or prevented (objectives may be on dose-response, type of patient, frequency of dosing, or other identifiers of safety and efficacy) and Phase IIB which are the most rigorous trials designed to demonstrate efficacy. The development process usually fails during this Phase II when the drug is discovered not to work as planned or to have toxic effects.

3. Phase III trials are the full scale evaluation of treatment and are designed to compare efficacy of the new treatment with the standard treatment. These are the most rigorous and extensive type of scientific clinical investigation of a new treatment. This is the “pre-marketing phase” of clinical trials. These are usually the most expensive and time-consuming of the trials. The trials may be difficult to design and run. Large groups (100 to 3000 subjects) are recruited and trial designs have included randomized controlled trials (parallel design), uncontrolled trials (single treatment), historical controls, no-randomized concurrent trials, factorial designs, and group sequential designs. Patients are monitored by the clinical researcher and personal physician. Phase III clinical trials may be divided into Phase IIIA which are trials done after efficacy of the therapy is demonstrated but before regulatory submission of a New Drug Application (NDA) or other dossier.

4. Upon authorization by the FDA, therapies determined to have proven safety, efficacy and quality may be made available to the general population. Patients and their physicians have expectations of benefit. However, not all safety or efficacy issues have been determined. The FDA requires continued evaluation after release to evaluate safety signs that may affect the benefit-risk ratio [57] [58]. These Phase IV studies include “all studies (other than routine surveillance) performed after drug approval and related to the approved indication” [55]. These are post-marketing surveillance studies. The focus of the trials is on how drugs work in the real world. Anyone seeking treatment from their physician may be treated with the therapy. Their personal physician monitors the results of treatment. Efficacy and detection of rare or long-term adverse effects over a much larger patient population and longer time period are evaluated, healthcare costs and outcomes are determined, and pharmacogenetics are studied. New clinical indications for a drug may be established and large number of patients and physicians are involved [59]. The FDA may require that a developer conduct a Phase IV trial as a stipulation for drug approval. Less than half of studies are completed or even initiated by developers [60]. Phase IV trials may result in a drug being removed from the market or restricted to certain indications.

5. This translational research is designed to “move from bench to bedside”. Phase V clinical trials refer to comparative effectiveness research and community-based research. Research is done on data collected. All reported uses are evaluated. Patients are not monitored. Its main focus is to determine integration of a new therapy into wide spread clinical practice. Filed under: cornell cooperative extension, evidence-based living, policy, the learning center tagged with: cooperative extension programs, evaluation, evidence-based programs, research methods, research translation.

Summary

The final outcome of clinical trials is improved clinical medicine. Understanding the steps to bring a new therapy to the general population provides clinicians insight into their staged development and timeline to availability. By improving developmental strategies and studies, time to availability to the general public with resulting benefit should result in better patient outcomes and fewer morbidities.

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