Abstract
Phase IV trials, studies conducted in the post-marketing scenario, are usually performed with a large number of patients and heterogeneous populations. They can be used to increase the generalizability of findings from phase III trials, to evaluate uncommon adverse events, and sometimes to assess cost-effectiveness. In oncology, phase IV trials also encompass the concept of “compassionate use”, where patients are given access to new therapies when enrollment in clinical trials is not feasible. Recently, regulatory agencies have started requesting phase IV studies for approved drugs; however, only 25% of marketed drugs go beyond mandatory phase III trials. Several study designs have been described for phase IV trials, but this is still a sparsely regulated area.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Gad SC. Clinical trials handbook. 1st ed. New York: Wiley; 2009. ISBN-13: 978-0471213888; ISBN-10: 0471213888
Hill TP. Conducting phase IV clinical studies: a moral imperative? Ecancermedicalscience. 2012;6(PMCID: PMC3493021):276.
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):2215–20. PMID: 11980521
Strom BL. Potential for conflict of interest in the evaluation of suspected adverse drug reactions: a counterpoint. JAMA. 2004;292(21):2643–6. PMID: 15572722
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/DataStandardsManualmonographs/default.htm. Accessed 16 Apr 2017.
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002877.pdf. Accessed 16 Apr 2017.
Ferguson L. External validity, generalizability, and knowledge utilization. J Nurs Scholarsh. 2004;36(1):16–22. PMID: 15098414
https://www.fda.gov/NewsEvents/PublicHealthFocus/ExpandedAccessCompassionateUse/. Accessed 26 Apr 2017.
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM351261.pdf. Accessed 26 Apr 2017.
Iudicello A, Alberghini L, Benini G, Mosconi P. Expanded Access Programme: looking for a common definition. Trials. 2016;17:21.
Brower A. Phase 4 research grows despite lack of FDA oversight. Biotechnol Healthc. 2007;4(5):16–22.
Glasser SP, Salas M, Delzell E. Importance and challenges of studying marketed drugs: what is a phase IV study? Common clinical research designs, registries, and self-reporting systems. J Clin Pharmacol. 2007;47(9):1074–86.
Suvarna V, Phase IV. Of drug development. Perspect Clin Res. 2010;1(2):57–60. PMID: 21829783
Moreno C, Montillo M, Panayiotidis P, Dimou M, Bloor A, Dupuis J, Schuh A, Norin S, Geisler C, Hillmen P, Doubek M, Trněný M, Obrtlikova P, Laurenti L, Stilgenbauer S, Smolej L, Ghia P, Cymbalista F, Jaeger U, Stamatopoulos K, Stavroyianni N, Carrington P, Zouabi H, Leblond V, Gomez Garcia JC, Rubio M, Marasca R, Musuraca G, Rigacci L, Farina L, Paolini R, Pospisilova S, Kimby E, Bradley C, Montserrat E. Ofatumumab in poor-prognosis chronic lymphocytic leukemia: a Phase IV, non-interventional, observational study from the European Research Initiative on Chronic Lymphocytic Leukemia. Haematologica. 2015;100(4):511–6.
Crino L, Dansin E, Garrido P, et al. Safety and efficacy of first-line bevacizumab-based therapy in advanced non- squamous non-small-cell lung cancer (SAiL, MO19390): a phase 4 study. Lancet Oncol. 2010;11:733–40.
Komatsu Y, Ohki E, Ueno N, Yoshida A, Toyoshima Y, Ueda E, Houzawa H, Togo K, Nishida T. Safety, efficacy and prognostic analyses of sunitinib in the post-marketing surveillance study of Japanese patients with gastrointestinal stromal tumor. Jpn J Clin Oncol. 2015;45(11):1016–22.
Edwards BJ, Raisch DW, Saraykar SS, Sun M, Hammel JA, Tran HT, Wehr N, Arabyat R, West DP. Hepatotoxicity with Vismodegib: an MD Anderson Cancer Center and Research on Adverse Drug Events and Reports Project. Drugs R D. 2017;17(1):211–8. PMID: 28063021
Patel MM, López-Collada VR, Bulhões MM, De Oliveira LH, Bautista Márquez A, Flannery B, Esparza-Aguilar M, Montenegro Renoiner EI, Luna-Cruz ME, Sato HK, Hernández-Hernández Ldel C, Toledo-Cortina G, Cerón-Rodríguez M, Osnaya-Romero N, Martínez-Alcazar M, Aguinaga-Villasenor RG, Plascencia-Hernández A, Fojaco-González F, Hernández-Peredo Rezk G, Gutierrez-Ramírez SF, Dorame-Castillo R, Tinajero-Pizano R, Mercado-Villegas B, Barbosa MR, Maluf EM, Ferreira LB, de Carvalho FM, dos Santos AR, Cesar ED, de Oliveira ME, Silva CL, de Los Angeles Cortes M, Ruiz Matus C, Tate J, Gargiullo P, Parashar UD. Intussusception risk and health benefits of rotavirus vaccination in Mexico and Brazil. N Engl J Med. 2011;364(24):2283–92. https://doi.org/10.1056/NEJMoa1012952. PMID: 21675888.
Durán CE, Christiaens T, Acosta Á, Vander Stichele R. Systematic review of cross-national drug utilization studies in Latin America: methods and comparability. Pharmacoepidemiol Drug Saf. 2016;25(1):16–25. PMID: 26486230
Driessen RJ, Boezeman JB, van de Kerkhof PC, de Jong EM. Three-year registry data on biological treatment for psoriasis: the influence of patient characteristics on treatment outcome. Br J Dermatol. 2009;160(3):670–5. PMID: 19210502
Riechelmann R, Srimuninnimit V, Kavan P, Di Bartolomeo M, Maiello E, Cicin I, Kröning H, Garcia-Alfonso P, Chau I, Fernández-Martos C, Ter-Ovanesov M, Peeters M, Picard P, Bordonaro R. Aflibercept plus FOLFIRI for 2nd line treatment of metastatic colorectal cancer (mCRC): long-term safety observation from the global aflibercept safety and quality-of-life (QoL) program (ASQoP). Ann Oncol. 2016;27(Suppl 6):552P. https://doi.org/10.1093/annonc/mdw370.100.
Eypasch E, Lefering R, Kum CK, Troidl H. Probability of adverse events that have not yet occurred: a statistical reminder. BMJ. 1995;311(7005):619–20. PubMed: 7663258
Castle WM, Lewis JA. Postmarketing surveillance of adverse drug reactions. Br Med J (Clin Res Ed). 1984;288:1458–9.
James WP, Caterson ID, Coutinho W, et al. Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med. 2010;363(10):905–17. PubMed: 20818901
Bonell CP, Hargreaves J, Cousens S, et al. Alternatives to randomization in the evaluation of public health interventions: design challenges and solutions. J Epidemiol Community Health. 2011;65(7):582.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer International Publishing AG, part of Springer Nature
About this chapter
Cite this chapter
Uema, D., Yen, C.T., Hinke, A., de Castro, G. (2018). Phase IV Trials: Interventional and Non-interventional Studies. In: Araújo, R., Riechelmann, R. (eds) Methods and Biostatistics in Oncology. Springer, Cham. https://doi.org/10.1007/978-3-319-71324-3_13
Download citation
DOI: https://doi.org/10.1007/978-3-319-71324-3_13
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-71323-6
Online ISBN: 978-3-319-71324-3
eBook Packages: MedicineMedicine (R0)