Phase IV Trials: Interventional and Non-interventional Studies

  • Deise Uema
  • Cheng Tzu Yen
  • Axel Hinke
  • Gilberto de CastroJr.


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.


Phase IV Interventional study Non-interventional study Cancer Oncology External validity Generalizability Uncommon adverse events Interactions Cost-effectiveness Compassionate use 


  1. 1.
    Gad SC. Clinical trials handbook. 1st ed. New York: Wiley; 2009. ISBN-13: 978-0471213888; ISBN-10: 0471213888Google Scholar
  2. 2.
    Hill TP. Conducting phase IV clinical studies: a moral imperative? Ecancermedicalscience. 2012;6(PMCID: PMC3493021):276.PubMedCentralGoogle Scholar
  3. 3.
    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: 11980521CrossRefPubMedGoogle Scholar
  4. 4.
    Strom BL. Potential for conflict of interest in the evaluation of suspected adverse drug reactions: a counterpoint. JAMA. 2004;292(21):2643–6. PMID: 15572722CrossRefPubMedGoogle Scholar
  5. 5.
  6. 6.
  7. 7.
    Ferguson L. External validity, generalizability, and knowledge utilization. J Nurs Scholarsh. 2004;36(1):16–22. PMID: 15098414CrossRefPubMedGoogle Scholar
  8. 8.
  9. 9.
  10. 10.
    Iudicello A, Alberghini L, Benini G, Mosconi P. Expanded Access Programme: looking for a common definition. Trials. 2016;17:21.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Brower A. Phase 4 research grows despite lack of FDA oversight. Biotechnol Healthc. 2007;4(5):16–22.PubMedPubMedCentralGoogle Scholar
  12. 12.
    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.CrossRefPubMedGoogle Scholar
  13. 13.
    Suvarna V, Phase IV. Of drug development. Perspect Clin Res. 2010;1(2):57–60. PMID: 21829783PubMedPubMedCentralGoogle Scholar
  14. 14.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    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.CrossRefPubMedGoogle Scholar
  16. 16.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    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: 28063021CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    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. PMID: 21675888.CrossRefPubMedGoogle Scholar
  19. 19.
    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: 26486230CrossRefPubMedGoogle Scholar
  20. 20.
    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: 19210502CrossRefPubMedGoogle Scholar
  21. 21.
    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. Scholar
  22. 22.
    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: 7663258CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Castle WM, Lewis JA. Postmarketing surveillance of adverse drug reactions. Br Med J (Clin Res Ed). 1984;288:1458–9.CrossRefGoogle Scholar
  24. 24.
    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: 20818901CrossRefPubMedGoogle Scholar
  25. 25.
    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.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Deise Uema
    • 1
    • 2
  • Cheng Tzu Yen
    • 3
  • Axel Hinke
    • 4
  • Gilberto de CastroJr.
    • 1
    • 2
  1. 1.ICESP—Medicine School of University of São PauloSão PauloBrazil
  2. 2.Sirio Libanês HospitalSão PauloBrazil
  3. 3.Oswaldo Cruz German HospitalSão PauloBrazil
  4. 4.WiSP Research InstituteLangenfeldGermany

Personalised recommendations