Education And Debate

The controlled clinical trial turns 100 years: Fibiger's trial of serum treatment of diphtheria

BMJ 1998; 317 doi: https://doi.org/10.1136/bmj.317.7167.1243 (Published 31 October 1998) Cite this as: BMJ 1998;317:1243
  1. Asbj⊘rn Hróbjartsson, PhD studenta,
  2. Peter C G⊘tzsche, directora,
  3. Christian Gluud, chief physician (cgluud@ipm.hosp.dk)b
  1. aNordic Cochrane Centre, H:S Rigshospitalet, Tagensvej 18 B, DK-2200 Copenhagen N, Denmark
  2. bCopenhagen Trial Unit, Centre for Clinical Intervention Research, Institute of Preventive Medicine, Copenhagen University Hospital, H:S Kommunehospitalet, DK-1399 Copenhagen K
  1. Correspondence to: Dr Gluud
  • Accepted 5 October 1998

The British Medical Research Council's trial of streptomycin for pulmonary tuberculosis, published in 1948,1 has been proposed as the first randomised trial in which random numbers were used and allocation of patients was effectively concealed. Before 1948 several randomised trials had been reported,2 but the method of randomisation was either not stated3 or was open to selection bias—for example, randomisation with use of a deck of cards.4

The earliest of these trials was published in 1898.5 It investigated the effect of serum treatment on diphtheria and was conducted by the Danish Nobel laureate, Johannes Fibiger. It was the first clinical trial in which random allocation was used and emphasised as a pivotal methodological principle. This pioneering improvement in methodology, combined with a large number of patients and rigorous planning, conduct, and reporting, makes the trial a milestone in the history of clinical trials.

Fibiger's trial was published in Danish and its method of randomisation has often been quoted incorrectly. We have translated central passages into English (available on the BMJwebsite at www.bmj.com) and discussed its methodological merit.

Summary points

A large randomised clinical trial was performed as early as 1898

Random allocation was emphasised as a central methodological principle

Patients were allocated to serum or no serum according to day of admittance, which created two comparable groups

The planning, conduct, and reporting of the trial was of high quality

The efficacy of serum treatment on diphtheria was shown

The trial was the first properly conducted controlled clinical trial

Fibiger and his trial

Johannes A G Fibiger (1867-1928) was born in Silkeborg, Denmark (figure). After receiving his medical degree in 1890 from the University of Copenhagen he visited Robert Koch and Emil von Behring in Germany. In 1895 Fibiger was awarded a doctoral degree for a thesis on diphtheria from the …

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