Regulatory Approval Of Pharmaceuticals Without A Randomised Controlled Study: Analysis Of Ema And Fda Approvals 1999–2014
Authors: Anthony J Hatswell, Gianluca Baio, Jesse A Berlin, Alar Irs, Nick Freemantle
Abstract:
Introduction: This study aims to explore the prevalence and characteristics of pharmaceutical approvals without randomized controlled trial (RCT) evidence in the regulatory decisions of the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) over the past 15 years.
Objective: To investigate the number and types of approvals granted without RCT evidence by the EMA and FDA between 1999 and 2014.
Methods: Data on drug approvals were obtained from the EMA website and the 'Drugs@FDA' database, covering the period from January 1, 1999, to May 8, 2014. Relevant information was extracted, including therapeutic area, type of approval, and review period.
Results:
During the study period, a total of 76 unique indications were granted without RCT results (44 by the EMA and 60 by the FDA), indicating a significant number of treatments reaching the market without undergoing an RCT. The majority of these approvals were for haematological malignancies (34), followed by oncology (15) and metabolic conditions (15). In cases where both agencies reviewed comparable data packages, the FDA granted more approvals (43 out of 44 vs. 35 out of 44) and had shorter review times (8.7 vs. 15.5 months). Additionally, products were launched earlier in the USA in 30 out of 34 cases, mainly due to companies submitting applications to the FDA before the EMA and faster FDA review times.
Discussion:
While approvals without RCT evidence are common, there is a lack of systematic monitoring to ensure the effectiveness and consistency of these treatments. This calls for an open debate on the role of marketing authorizations granted without RCT results, as well as the development of guidelines to determine acceptable data packages for regulatory agencies.
Conclusion:
Pharmaceutical indications are frequently approved without controlled trial results, particularly in solid and haematological malignancies. The level of evidence provided by companies for marketing authorizations appears to be inconsistent. While there are slight differences between the EU and the USA in terms of approvals, the agencies generally reach similar decisions. However, the significant differences in approval timing warrant attention. Harmonization of regulatory processes, where feasible, is recommended to reduce delays between submissions. Additionally, there is a need to reevaluate the role of uncontrolled studies in drug approvals and establish formal guidance on acceptable data packages, which should be debated among regulators, companies, and physicians.
Citation: Anthony J Hatswell, Gianluca Baio, Jesse A Berlin, Alar Irs, Nick Freemantle Regulatory Approval Of Pharmaceuticals Without A Randomised Controlled Study: Analysis Of Ema And Fda Approvals 1999–2014 BMJ Open 2016;6:e011666 doi:10.1136/bmjopen-2016-011666.
Received: 25 February 2016 Revised: 27 May 2016 Accepted: 1 June 2016 Published: 30 June 2016
Copyright: This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.See: http://creativecommons.org/licenses/by-nc/4.0/
Contributors
AJH is a health economist specialising in the modelling and health technology assessment of pharmaceuticals, GB a Reader in Statistics and Health Economics at the University College London specialising in Bayesian biostatistics, JAB was a Professor of Biostatistics before moving to epidemiology department in Johnson & Johnson, AI is a Clinical Pharmacologist who sits on the Committee for Human Medicinal Products of the European Medicines Agency, NF is a Professor of Clinical Epidemiology & Biostatistics with over 25 years experience in clinical trials and regulatory affairs. The review of treatments was conducted by AJH with data taken from the websites of the EMA and FDA, with the article jointly written by all authors. NF is the guarantor.
Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests
AJH works for Bresmed, an agency which undertakes contract research for the pharmaceutical industry. GB holds a research grant from Mapi, a consultancy company working in the area of health economic evaluation and has consulted with Sanofi Pasteur, GSK and Novartis on economic analysis of pharmaceutical products. JAB is a full-time employee of Johnson & Johnson and holds stock. AI is employed by the Estonian Agency of Medicines (EAM) and is a member of the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use. NF has consulted with Ipsen which has conducted single-arm trials of products for regulatory purposes, and with Sanofi Aventis, Lundbeck and Novo Nordisk on the design of randomised trials. The views expressed in this article are those of the authors and should not be interpreted as those of their employers.
