Abstract
Clinical trials become very relevant in the development of new drugs when their pharmacokinetics, pharmacodynamics, efficiency, safety and possible adverse effects are being assessed. So new drugs are available for their daily use in patients, a model has been proposed for more than four decades; This model consists in the realization of sequential research studies, which were called clinical phases I, II, III and IV, which begin once the drugs’ effects have been verified in cellular and animal models (preclinical phase). In this article, the general characteristics of each of the clinical phases are synthesized but, apart from that, the modifications that have been done over the years are described with the purpose of making new drugs available in a quicker way.
References
Umscheid CA, Margolis DJ, Grossman CE. Key concepts of clinical trials: a narrative review. Postgrad Med. 2011;123(5):194-204. DOI: 10.3810/pgm.2011.09.2475
Issa NT, Wathieu H, Ojo A, Byers SW, Dakshanamurthy S. Drug metabolism in preclinical drug development: a survey of the discovery process, toxicology, and computational tools. Curr Drug Metab. 2017;18(6):556-565. DOI: 10.2174/1389200218666170316093301
Temple R. Current definitions of phases of investigation and the role of the FDA in the conduct of clinical trials. Am Heart J. 2000;139(4):S133-S135. DOI: 10.1016/S0002-8703(00)90060-7
Lazcano-Ponce E, Salazar-Martínez E, Gutiérrez-Castrellón P, Angeles-Llerenas A, Hernández-Garduño A, Viramontes JL. Randomized clinical trials: variants, randomization methods, analysis, ethical issues and regulations. Salud Publica Mex. 2004;46(6):559-584. DOI: 10.1590/s0036-36342004000600012
Villasís-Keever MA, Miranda-Novales MG. El protocolo de investigación II: los diseños de estudio para investigación clínica. Rev Alerg Mex. 2016;63(1):80-90. DOI: 10.29262/ram.v63i1.163
Kay SC, Luke DG, Tamer HR. ASHP guidelines for the management of investigational drug products. Am J Health Syst Pharm. 2018;75(8):561-573. DOI: 10.2146/ajhp170812
Ivy SP, Siu LL, Garrett-Mayer E, Rubinstein L. Approaches to phase 1 clinical trial design focused on safety, efficiency, and selected patient populations: a report from the clinical trial design task force of the national cancer institute investigational drug steering committee. Clin Cancer Res. 2010;16(6):1726-1736. DOI: 10.1158/1078-0432.CCR-09-1961
Coates S, Täubel J, Lorch U. Practical risk management in early phase clinical trials. Eur J Clin Pharmacol. 2019;75(4):483-496. DOI: 10.1007/s00228-018-02607-8.
Mahipal A, Nguyen D. Risk and benefits of phase 1 clinical trial participation. Cancer Control. 2014:21(3):193-199. DOI: 10.1177/107327481402100303
Chen EX, Tannock IF. Risk and benefits of phase 1 clinical trials evaluating new anticancer agents: a case for more innovation. JAMA. 2004;292(17):2150-2151. DOI: 10.1001/jama.292.17.2150
Yao B, Zhu L, Jiang Q, Xia HA. Safety monitoring in clinical trials. Pharmaceutics. 2013;5(1):94-106. DOI: 10.3390/pharmaceutics5010094
International Conference on Harmonization. ICH harmonized tripartite guideline. Guideline for good clinical practice E6(R1). International Conference on Harmonization; 1996.
Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC. Bélgica: European Commission; 2014.
Committee for Medicinal Products for Human Use. Guideline on strategies to identify and mitigate risks for first-in-human clinical trials with investigational medicinal products. Inglaterra: Committee for Medicinal Products for Human Use; 2007.
Kenter MJ, Cohen AF. Establishing risk of human experimentation with drugs: lessons from TGN1412. Lancet. 2006;368(9544):1387-1391. DOI: 10.1016/S0140-6736(06)69562-7
Schwartz D, Lellouch J. Explanatory and pragmatic attitudes in therapeutical trials. J Chronic Dis. 2009;6(5):499-505. DOI: 10.1016/j.jclinepi.2009.01.012
Treweek S, Zwarenstein M. Making trials matter: pragmatic and explanatory trials and the problem of applicability. Trials. 2009;10:37. DOI: 10.1186/1745-6215-10-37.
Tuech JJ, Moutel G, Pessaux P, Thoma V, Schraub S, Herve C. Disclosure of competing financial interests and role of sponsors in phase III cancer trials. Eur J Cancer. 2005;41(15):2237-2240. DOI: 10.1016/j.ejca.2004.12.036
Directive 2001/83/EC on the Community Code Relating to Medicinal Products for Human Use. Bélgica: European Commission; 20148.
European Medicines Agency. Scientific guidance on post-authorization efficacy studies. Países Bajos: European Medicines Agency; 2015.
Gale EA. Post-marketing studies of new insulins: sales or science? BMJ. 2012;344:e3974. DOI: 10.1136/bmj.e3974
Lasser KE, Allen PD, Woolhandler SJ, Himmelstein DU, Wolfe SM, Bor DH. Timing of new black box warnings and withdrawals for prescription medications. JAMA. 2002;287(17):2215-2220. DOI: 10.1001/jama.287.17.2215
Zhang X, Zhang Y, Ye X, Guo X, Zhang T, He J. Overview of phase IV clinical trials for postmarket drug safety surveillance: a status report from the ClinicalTrials.gov registry. BMJ Open. 2016;6(11):e010643. DOI: 10.1136/bmjopen-2015-010643
Suvarna V. Phase IV of drug development. Perspect Clin Res 2010;1: 57-60.
Italiano A, Massard C, Bahleda R, Vataire AL, Deutsch E, Magné N, et al. Treatment outcome and survival in participants in phase 1 oncology trials carried out from 2003 to 2006 at Institute Gustave Roussy. Ann Oncol. 2008;19(4):787-792. DOI: 10.1093/annonc/mdm548
Horstmann E, McCabe MS, Grochow L, Yamamoto S, Budd T, Shoemaker D, et al. Risks and benefits of phase 1 oncology trials. 1991 through 2002. N Engl J Med. 2005;352(9):895-904. DOI: 10.1056/NEJMsa042220
Thall PF, Cook JD. Dose-finding based on efficacy-toxicity trade-offs. Biometrics. 2004;60(3):684-693. DOI: 10.1111/j.0006-341X.2004.00218.x
Yin G, Li Y, Ji Y. Bayesian dose finding in phase I/II clinical trials using toxicity and efficacy odds ratio. Biometrics. 2006;62(3):777-787. DOI: 10.1111/j.1541-0420.2006.00534.x
Wages NA, Conaway MR. Phase I/II adaptive design for drug combination oncology trials. Stat Med. 2014;33(12):1990-2003. DOI: 10.1002/sim.6097
Braun TM. The bivariate continual reassessment method. Extending the CRM to phase I trials of two competing outcomes. Control Clin Trials. 2002;23(3):240-256. DOI: 10.1016/S0197-2456(01)00205-7
O’Quigley J, Conaway MR,. Extended model-based desings for more complex dose-finding studies. Stat Med. 2011;30(17):2062-2069. DOI: 10.1002/sim.4024
Wages NA, O’Quigley J, Conaway MR. Phase I design for completely for partially ordered treatment schedules. Stat Med. 2014;33(4):569-579. DOI: 10.1002/sim.5998
Mistry P, Dunn JA, Marshall A. A literature review of applied adaptive design methodology within the field of oncology in randomised controlled trials and a proposed extension to the CONSORT guidelines. BMC Med Res Methodol. 2017;17(1):108. DOI: 10.1186/s12874-017-0393-6
Bothwell LE, Avorn J, Khan NF, Kesselheim AS. Adaptive design clinical trials: a review of the literature and ClinicalTrials.gov. BMJ Open. 2018;8(2):e018320. DOI: 10.1136/bmjopen-2017-018320
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Copyright (c) 2019 Revista Alergia México