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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


Introduction The efficacy of pharmaceuticals is most often demonstrated by randomised controlled trials (RCTs); however, in some cases, regulatory applications lack RCT evidence.


To investigate the number and type of these approvals over the past 15 years by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA).


Drug approval data were downloaded from the EMA website and the ‘Drugs@FDA’ database for all decisions on pharmaceuticals published from 1 January 1999 to 8 May 2014. The details of eligible applications were extracted, including the therapeutic area, type of approval and review period.


Over the period of the study, 76 unique indications were granted without RCT results (44 by the EMA and 60 by the FDA), demonstrating that a substantial number of treatments reach the market without undergoing an RCT. The majority was for haematological malignancies (34), with the next most common areas being oncology (15) and metabolic conditions (15). Of the applications made to both agencies with a comparable data package, the FDA granted more approvals (43/44 vs 35/44) and took less time to review products (8.7 vs 15.5 months). Products reached the market first in the USA in 30 of 34 cases (mean 13.1 months) due to companies making FDA submission before EMA submissions and faster FDA review time.


Despite the frequency with which approvals are granted without RCT results, there is no systematic monitoring of such treatments to confirm their effectiveness or consistency regarding when this form of evidence is appropriate. We recommend a more open debate on the role of marketing authorisations granted without RCT results, and the development of guidelines on what constitutes an acceptable data package for regulators.


Newly licensed pharmaceutical indications are frequently approved without any controlled trial results, particularly in solid and haematological malignancies. While some agents showed such high levels of effectiveness that an RCT is unlikely to have changed any decision, the level of evidence provided by companies to support marketing authorisations does appear to be inconsistent. In the more complex cases (particularly those treatments not approved by one agency), it is not always clear that the conduct of an RCT was impractical.

Although there appears to be a slight difference between approvals in the EU and the USA (with the FDA more likely to grant a positive approval in oncology), the agencies broadly reach the same decisions. However, the systematic differences in approval timing are of particular interest and concern. We therefore suggest that regulatory agencies should continue to harmonise processes where practical (to reduce delays between submissions). In parallel to this, given the frequency at which uncontrolled studies occur, their role in drug approval requires reappraisal, with formal guidance on what represents an acceptable data package; this should then be debated by 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:


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.

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