Evidence map›Paper›PMID 27363818›Full record

ArticleBMJ open2016

Regulatory approval of pharmaceuticals without a randomised controlled study: analysis of EMA and FDA approvals 1999-2014.

Anthony J Hatswell, Gianluca Baio, Jesse A Berlin, Alar Irs, Nick Freemantle

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in BMJ open, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 74 papers, 7 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
74citing papers in PubMed, 7 pooled it
17.0field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

74 citing papers in PubMed, 7 syntheses or guidelines pooled it, 187 citations in OpenAlex.

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  20. On the use of external controls in clinical trials.Journal of the National Cancer Institute. Monographs · 2025
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14 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

5 authors at 3 institutions in 3 countries.

Anthony J HatswellDepartment of Statistical Science, University College London, London, UK.
Gianluca BaioDepartment of Statistical Science, University College London, London, UK.
Jesse A BerlinJohnson & Johnson, Titusville, New Jersey, USA.
Alar IrsDepartment of Pharmacology, University of Tartu, Tartu, Estonia.
Nick FreemantleDepartment of Primary Care & Population Health, University College London, London, UK.
University College London · GBJohnson & Johnson (United States) · USUniversity of Tartu · EE

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

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

objectiveTo 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).

methodsDrug 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.

resultsOver 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. DISCUSSION: 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.

Indexed as

Antineoplastic AgentsDrug ApprovalEuropeGovernment AgenciesHumansProduct Surveillance, PostmarketingRandomized Controlled Trials as TopicUnited StatesUnited States Food and Drug AdministrationAntineoplastic AgentsCLINICAL PHARMACOLOGYRegulatory

Identifiers

PMID27363818
PMCPMC4932294
OpenAlexW2464447852

What OpenQuestion holds

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LicenceCC BY-NC
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.