Design and regulation of clinical trials; from the laboratory to the pharmacy (original) (raw)
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Borneo Journal of Pharmacy, 2023
The research carried out to find a better treatment, improve healthcare, and benefit the current medical practice is termed clinical research. Clinical trial includes the pharmacodynamics (mechanisms of action of a new drug), pharmacokinetics (drug metabolism inside the body), therapeutics (efficacy of the drug), and adverse effects (safety of the drug) of the novel medical products. Clinical research is a process that involves human subjects and their biological specimens. The clinical trial is a meticulously planned protocol-based study of a drug/device to discover a new/better way to prevent, diagnose, and treat a disease/illness. Considering the involvement of both healthy and diseased people in clinical trials, the regulatory authorities have a significant role in the processes involving the conduction of clinical research and carefully evaluate their potential implications on humans. Because clinical trials are usually aimed at assessing the safety and efficacy of novel pharmaceutical compounds and medical devices, pharmacovigilance laws and risk management assume increased significance while conducting clinical research/trials. In this review, we attempt to discuss the regulatory authorities' roles in different geographical regions, including the United States of America, The European Union, and India. We also focus on the importance of pharmacovigilance laws and risk management during clinical trials.
Planning Clinical Trials: The Main Step in Developing New Drugs
SOJ Pharmacy & Pharmaceutical Sciences
A therapeutic trial is generally conducted to determine a new treatment or improve therapeutic applications. Several crucial questions should be considered before the trial is undertaken. The planning of a clinical trial involves a succession of steps intended to develop a protocol providing a clear and unbiased answer to a precise therapeutic question. What treatments are to be compared? What type of population should be studied? What are the evaluation criteria? What is the most suitable experimental scheme? How many patients should be included? What statistical procedures should be implemented (single analysis, intermediary analysis, serial analysis)? This paper considers briefly the main points to be resolved at each planning stage.
Brazilian Journal of Medical and Biological Research, 2016
The process of drug development involves non-clinical and clinical studies. Non-clinical studies are conducted using different protocols including animal studies, which mostly follow the Good Laboratory Practice (GLP) regulations. During the early preclinical development process, also known as Go/No-Go decision, a drug candidate needs to pass through several steps, such as determination of drug availability (studies on pharmacokinetics), absorption, distribution, metabolism and elimination (ADME) and preliminary studies that aim to investigate the candidate safety including genotoxicity, mutagenicity, safety pharmacology and general toxicology. These preliminary studies generally do not need to comply with GLP regulations. These studies aim at investigating the drug safety to obtain the first information about its tolerability in different systems that are relevant for further decisions. There are, however, other studies that should be performed according to GLP standards and are mandatory for the safe exposure to humans, such as repeated dose toxicity, genotoxicity and safety pharmacology. These studies must be conducted before the Investigational New Drug (IND) application. The package of non-clinical studies should cover all information needed for the safe transposition of drugs from animals to humans, generally based on the non-observed adverse effect level (NOAEL) obtained from general toxicity studies. After IND approval, other GLP experiments for the evaluation of chronic toxicity, reproductive and developmental toxicity, carcinogenicity and genotoxicity, are carried out during the clinical phase of development. However, the necessity of performing such studies depends on the new drug clinical application purpose.
Clinical Trials of New Drug Products: What Gets Compared to Whom
American Journal of Clinical and Experimental Medicine, 2015
Two of the most controversial aspects of phase III clinical trial design are the choice of the control group(s) and the choice of the outcome variable(s). Each of these choices has overlapping scientific and ethical ramifications, and the tension between maximizing scientific validity on the one hand, and protecting the rights and welfare of the human participants in the trial on the other, is the main source of the controversy. The intensity of the debate is increased whenever these choices are motivated not by scientific or ethical principles, but are driven by conflicts of interest. And so it comes to pass that in testing the safety and efficacy of new drug products, when study design choices are made more to achieve rapid market approval than to accurately assess safety and efficacy, thereby putting the welfare of both the trial participants and future patients at risk, the public and its advocates will recoil. In this paper, we study two issues of this kind: the use of placebo controls when an established intervention for the condition under consideration exists, and the use of surrogate outcome measures. There is a rich and growing literature on both of these topics and we will have little to contribute to a greater theoretical understanding of either of them. Our aim is to point to the ethical ramifications of these choices in the context of clinical trials of new drug products, and to suggest how these choices may be better made to serve public health interests. What is to come is portended by the observation that, "In the United States, the long tradition of leaving to the pharmaceutical industry the task of evaluating the efficacy and safety of its products has permitted manufacturers to make study design choices that largely determine the shape of the answers eventually provided by the trials" (Psaty and Weiss, 2007, p. 330).
Specific recommendations to improve the design and conduct of clinical trials
Trials
There are many reasons why the majority of clinical trials fail or have limited applicability to patient care. These include restrictive entry criteria, short duration studies, unrecognized adverse drug effects, and reporting of therapy assignment preferential to actual use. Frequently, experimental animal models are used sparingly and do not accurately simulate human disease. We suggest two approaches to improve the conduct, increase the success, and applicability of clinical trials. Studies can apply dosing of the investigational therapeutics and outcomes, determined from animal models that more closely simulate human disease. More extensive identification of known and potential risk factors and confounding issues, gleaned from recently organized “big data,” should be utilized to create models for trials. The risk factors in each model are then accounted for and managed during each study.
Good clinical trials and good clinical practice
Revista portuguesa de cardiologia: orgao oficial da Sociedade Portuguesa de Cardiologia = Portuguese journal of cardiology: an official journal of the Portuguese Society of Cardiology
To analyze the quality of clinical trials in Japan for new applications of pharmaceuticals, compliance with the Good Clinical Practice (GCP) inspection was studied using Review Reports for approvals from fiscal year (FY)1999 to FY2008. Guidelines for GCP in Japan were harmonized with those of other countries at the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Both to protect human rights, safety and welfare and to perform clinical trials scientifically and ethically, ensuring conformity with GCP is necessary when evaluating the safety and efficacy of the clinical data in common technical documents (CTD). In the conformity audit service of the Office of Conformity Audit of Pharmaceuticals and Medical Devices Agency (PMDA), the conformity of the studies and the documents between application materials of CTD attached to application forms for approval and case report forms (CRFs) is reviewed by document-based conformity inspection, and the conformity between medical records and CRFs is reviewed by on-site GCP inspection including oversea inspection. The GCP inspection includes both the on-site GCP inspection and the documentbased conformity inspection. The importance of the GCP inspection by the Office of Conformity Audit to protect human rights, safety and welfare is summarized in this study. In conclusion, GCP inspection is conducted in accordance with the latest GCP, and the quality of clinical trials in Japan meets the Review Process by PMDA for marketing authorization. I hope that the GCP inspection protects human rights and improves the GCP conformity of clinical trials in Japan.