Abstract
Health authorities throughout the world have regulations for requesting additional research in the post-approval setting. This chapter focuses on the regulations in the USA and European Union (EU). The history of post-approval studies can be traced through changing regulations enforced by the US Food and Drug Administration (FDA) and the EU European Medicines Agency (EMA).
Post-approval studies are either clinical trials (interventional) or observational (non-interventional) studies. Choosing a study design may be influenced by the strengths and weaknesses of the design options and available data sources.
Imposed post-approval studies are reviewed for compliance by the regulatory agencies. For clinical trials that are ongoing at the time of approval, often these are classified as post-marketing commitment (PMC) in the USA or post-authorization measure (PAM) in the EU. Findings of these trials can be submitted to the health authorities for addition to the prescribing information. The FDA and EMA both track progress on PMC/PMRs and PAMs, respectively.
Post-approval studies are necessary to continually gather data on the safety and effectiveness of approved drugs. These studies are regulated by health authorities, included in registries (e.g., ClinicalTrials.gov, ENCePP), and tracked to completion. This chapter reviews the history of the regulations, terminology, study designs, and systematic reviews of the published post-approval studies.
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Abbreviations
- CFR:
-
Code of Federal Regulations
- EMA:
-
European Medicines Agency
- EU:
-
European Union
- FDA:
-
Food and Drug Administration
- FDAAA:
-
Food and drug Administration Amendments Act
- MAH:
-
Market authorization holder
- PAES:
-
Post-authorization efficacy study
- PAM:
-
Post-authorization measure
- PAS:
-
Post-authorization study
- PASS:
-
Post-authorization safety study
- PMC:
-
Post-marketing commitment
- PMR:
-
Post-marketing requirement
- PREA:
-
Pediatric Research Equity Act
- REMS:
-
Risk evaluation and mitigation strategy
- USA:
-
United States
References
Austin PC (2011) An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav Res 46(3):399–424
Austin PC, Stuart EA (2015) Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies. Stat Med 34(28):3661–3679
Beaver JA, Howie LN, Pelosof L, Kim T, Liu J, Goldberg KB, Sridhara R, Blumenthal GM, Farrell AT, Keegan P, Pazdur R, Kluetz PG (2018) A 25-year experience of US Food and Drug Administration approval of malignant hematology and oncology drugs and biologics. JAMA Oncol. https://doi.org/10.1001/jamaoncol.2017.5618. Published online March 1, 2018
Berger ML, Dreyer N, Anderson F, Towse A, Sedrakyan A, Normand SL (2012) Prospective observational studies to assess comparative effectiveness: the ISPOR good research practices task force report. Value Health 15(2):217–230
Berger ML, Sox H, Willke RJ, Brixner DL, Eichler HG, Goettsch W, Madigan D, Makady A, Schneeweiss S, Tarricone R, Wang SV, Watkins J, Mullins CD (2017) Good practices for real-world data studies of treatment and/or comparative effectiveness: recommendations from the joint ISPOR-ISPE Special Task Force on real-world evidence in health care decision making. Pharmacoepidemiol Drug Saf 26(9):1033–1039
Berry DA, Elanshoff M, Blotner S, Davi R, Beineke P, Chandler M, Lee DS, Chen LC, Sarkar S (2017) Creating a synthetic control arm from previous clinical trials: Application to establishing early end points as indicators of overall survival in acute myeloid leukemia (AML). ASCO abstract. J Clin Oncol 35(15_Suppl):7021. https://doi.org/10.1200/JCO.2017.35.15_suppl.7021. Published online May 30, 2017. https://ascopubs.org/doi/full/10.1200/CCI.19.00037
Blake KV, Prilla S, Accadebled S, Guimier M, Biscaro M, Persson I, Arlett P, Blackburn S, Fitt H (2011) European Medicines Agency review of post-authorisation studies with implications for the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance. Pharmacoepidemiol Drug Saf 20:1021–1029
Blumenthal S (2017) The use of clinical registries in the United States: a landscape survey. EGEMS (Wash DC) 5(1):26. https://doi.org/10.5334/egems.248. Published 2017 Dec 7
Chou R, Helfand M (2005) Challenges in systematic reviews that assess treatment harms. Ann Intern Med 142(12 Pt 2):1090–1099
Dreyer NA, Schneeweiss S, McNeil B, Berger ML, Walker AM, Ollendorf DA, Gliklich RE, on behalf of the GRACE Initiative (2010) GRACE principles: recognizing high-quality observational studies of comparative effectiveness. Am J Manag Care 16:467–471
Engel P, Almas MF, DeBruin ML, Starzyk K, Blackburn S, Dreyer NA (2017) Lessons learned on the design and the conduct of Post-Authorization Safety Studies: review of 3 years of PRAC oversight. Br J Clin Pharmacol 83:884–893
European Medicines Agency (2012) Legal framework: pharmacovigilance. Available at https://www.ema.europa.eu/en/human-regulatory/overview/pharmacovigilance/legal-framework-pharmacovigilance. Accessed 12 June 2020
European Medicines Agency (2016) Scientific guidance on post-authorisation efficacy studies. Available at https://www.ema.europa.eu/en/documents/scientific-guideline/scientific-guidance-post-authorisation-efficacy-studies-first-version_en.pdf. Accessed 12 June 2020
European Medicines Agency (2017) Guideline on good pharmacovigilance practice (GVP). Available at https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-pharmacovigilance-practices-gvp-module-viii-post-authorisation-safety-studies-rev-3_en.pdf. Accessed 12 June 2020
European Medicines Agency (2020a) Post-authorisation safety studies (PASS). Available at https://www.ema.europa.eu/en/human-regulatory/post-authorisation/pharmacovigilance/post-authorisation-safety-studies-pass-0. Accessed 12 June 2020
European Medicines Agency (2020b) Post-authorisation measures: questions and answers. https://www.ema.europa.eu/en/human-regulatory/post-authorisation/post-authorisation-measures-questions-answers. Accessed 12 June 2020
European Network of Centers for Pharmacoepidemiology and Pharmacovigilance (ENCePP) (2010) Guidelines on methodological standards in Pharmacoepidemiology (Revision 7), 2010. Online: http://www.encepp.eu/standards_and_guidances/documents/ENCePPGuideonMethStandardsinPE_Rev7.pdf. Accessed 12 June 2020
European Network of Centers for Pharmacoepidemiology and Pharmacovigilance (ENCePP) (2017) Guidelines on Good Pharmacovigilance (GVP) – Module VIII – Post-authorization safety studies (Revision 3). Online: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-pharmacovigilance-practices-gvp-module-viii-post-authorisation-safety-studies-rev-3_en.pdf. Accessed 12 June 2020
Food and Drug Administration (2011) Guidance for industry postmarketing studies and clinical trials – implementation of section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act. Available at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM172001.pdf or https://www.fda.gov/regulatory-information/search-fda-guidance-documents/postmarketing-studies-and-clinical-trials-implementation-section-505o3-federal-food-drug-and. Accessed 12 June 2020
Food and Drug Administration (2013) Best practices for conducting and reporting pharmacoepidemiology safety studies using electronic healthcare data sets. May 2013. Online: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/best-practices-conducting-and-reporting-pharmacoepidemiologic-safety-studies-using-electronic. Accessed 12 June 2020
Food and Drug Administration (2018) FDA drug safety communication: new risk factor for Progressive Multifocal Leukoencephalopathy (PML) associated with Tysabri (natalizumab). Available at https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-new-risk-factor-progressive-multifocal-leukoencephalopathy-pml. Accessed 12 June 2020
Food and Drug Administration (2019) FDA in brief: FDA issues annual report on efforts to hold industry accountable for fulfilling critical post-marketing studies of the benefits, safety of new drugs. https://www.fda.gov/news-events/fda-brief/fda-brief-fda-issues-annual-report-efforts-hold-industry-accountable-fulfilling-critical-post. Accessed 12 June 2020
Food and Drug Administration (2020a) List of pregnancy exposure registries updated 17 Jan 2020. Online: https://www.fda.gov/science-research/womens-health-research/list-pregnancy-exposure-registries. Accessed 20 Feb 2020
Food and Drug Administration (2020b) Postmarketing requirements and commitments: reports. https://www.fda.gov/drugs/postmarket-requirements-and-commitments/postmarketing-requirements-and-commitments-reports. Accessed 12 June 2020
Gliklich R, Dreyer N, Leavy M (eds) (2014) Registries for evaluating patient outcomes: a user’s guide, 3rd edn. Two volumes. (Prepared by the Outcome DEcIDE Center [Outcome Sciences, Inc., a Quintiles company] under Contract No. 290 2005 00351 TO7.) AHRQ Publication No. 13(14)-EHC111. Agency for Healthcare Research and Quality, Rockville. http://www.effectivehealthcare.ahrq.gov/registries-guide-3.cfm
Goedecke T (2017) EU PASS/PAES Requirements for Disclosure. Available at https://www.ema.europa.eu/en/documents/presentation/presentation-eu-pass/paes-requirements-disclosure-thomas-goedecke_en.pdf. Accessed 12 June 2020
Hall GC, Sauer B, Bourke A, Brown JS, Reynolds MW, LoCasale R (2012) Guidelines for good database selection and use in pharmacoepidemiology research [published correction appears in Pharmacoepidemiol Drug Saf. 2012;21(11):1249. Casale, Robert Lo [corrected to LoCasale, Robert]]. Pharmacoepidemiol Drug Saf 21(1):1–10. https://doi.org/10.1002/pds.2229
International Society for Pharmacoepidemiology (2015) Guidelines for good pharmacoepidemiology practice (Revision 3), 2015. Online: https://www.pharmacoepi.org/resources/policies/guidelines-08027/#1. Accessed 12 June 2020
Kappos L, Bates D, Edan G, Eraksoy M, Garcia-Merino A, Grigoriadis N, Hartung HP, Havrdová E, Hillert J, Hohlfeld R, Kremenchutzky M, Lyon-Caen O, Miller A, Pozzilli C, Ravnborg M, Saida T, Sindic C, Vass K, Clifford DB, Hauser S, Major EO, O’Connor PW, Weiner HL, Clanet M, Gold R, Hirsch HH, Radü EW, Sørensen PS, King J (2011) Natalizumab treatment for multiple sclerosis: updated recommendations for patient selection and monitoring. Lancet Neurol 10(8):745–758
Krumholz HM, Ross JS, Presler AH, Egilman DS (2007) What have we learnt from Vioxx? BMJ 334(7585):120–123. https://doi.org/10.1136/bmj.39024.487720.68
Naci H, Smalley KR, Kesselheim AS (2017) Characteristics of preapproval and postapproval studies for drugs granted accelerated approval by the US Food and Drug Administration. JAMA 318(7):626–636. https://doi.org/10.1001/jama.2017.9415
National Institutes of Health (2019) List of registries, last reviewed 18 Nov 2019. Available at: https://www.nih.gov/health-information/nih-clinical-research-trials-you/list-registries. Accessed 12 June 2020
Patsopoulous NA (2011) A pragmatic view on pragmatic trials. Dialogues Clin Neurosci 13:217–224
Prakash S, Valentine V (2007) Timeline: the rise and fall of Vioxx November 10, 2007. https://www.npr.org/2007/11/10/5470430/timeline-the-rise-and-fall-of-vioxx
Rosenbaum PR, Rubin DB (2007) The central role of the propensity score in observational studies for causal effects. Biometrika 70(1 (Apr, 1983)):41–55
Suissa S (2007) Immortal time bias in observational studies of drug effects. Pharmacoepidemiol Drug Saf 16(3):241–249
Suissa S (2008) Immortal time bias in pharmaco-epidemiology. Am J Epidemiol 167(4):492–499
Wallach JD, Egilman AC, Dhruva SS, McCarthy ME, Miller JE, Woloshin S, Schwartz LM, Ross JS (2018) Postmarket studies required by the US Food and Drug Administration for new drugs and biologics approved between 2009 and 2012: cross sectional analysis. BMJ 361:k2031
Zauderer MG, Grigorenko A, May P, Kastango N, Wagner I, Caroline A (2019) Creating a synthetic clinical trial: comparative effectiveness analyses using electronic medical record. JCO Clin Cancer Inform. https://doi.org/10.1200/CCI.19.00037. Published online June 21, 2019
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Werther, W., Loughlin, A.M. (2021). Post-Approval Regulatory Requirements. In: Piantadosi, S., Meinert, C.L. (eds) Principles and Practice of Clinical Trials. Springer, Cham. https://doi.org/10.1007/978-3-319-52677-5_256-1
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DOI: https://doi.org/10.1007/978-3-319-52677-5_256-1
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