Research Methods & Ethics · 1948
MRC Streptomycin Trial for Pulmonary Tuberculosis
Medical Research Council Streptomycin Treatment of Pulmonary Tuberculosis Trial
In 1947, tuberculosis killed roughly 50,000 people in Britain annually, and the only established treatment was bed rest in a sanatorium, sometimes supplemented by surgical collapse of a diseased lung. Streptomycin had been isolated by Selman Waksman and Albert Schatz at Rutgers in 1943 and demonstrated bactericidal activity against Mycobacterium tuberculosis in vitro. The question of whether it worked in patients was urgent, but supplies were extremely limited; the United Kingdom had access to only a small amount of American-manufactured drug. That scarcity, paradoxically, made a controlled allocation ethically defensible and practically necessary.
Austin Bradford Hill, a statistician and epidemiologist at the Medical Research Council who had already thought carefully about how to evaluate therapies, designed an allocation scheme using sealed envelopes drawn from random number tables. The envelopes were prepared at MRC headquarters and sent to each participating hospital, where they were opened only after a patient was formally admitted to the trial. This concealment prevented clinicians from influencing which patients entered each arm. Hill enrolled 107 patients with acute bilateral pulmonary tuberculosis at multiple British centers: 55 were allocated to streptomycin plus bed rest, 52 to bed rest alone.
At six months, 7% of the streptomycin group had died, compared with 27% in the control arm. Radiographic assessments were conducted independently by two radiologists and one clinician, each unaware of the patient's treatment assignment, a precaution that addressed one of the more obvious sources of subjective bias in outcome measurement. The results appeared in the BMJ in October 1948 and were clear enough that no one seriously disputed the drug's short-term efficacy.
The trial also documented something troubling: a substantial proportion of streptomycin-treated survivors showed bacteriological evidence of drug resistance by six months. This was not merely a side observation. Hill and Philip D'Arcy Hart, who directed the MRC tuberculosis unit and led the clinical implementation, recognized that resistance would limit single-drug therapy. The finding directly motivated research into combined anti-tubercular regimens, first testing streptomycin with para-aminosalicylic acid, and eventually developing the isoniazid-containing protocols that transformed TB prognosis in the 1950s.
The methodological template the trial established was at least as consequential as its clinical result. Concealed random allocation, pre-specified primary outcomes, and blinded outcome adjudication were not entirely novel concepts, but this trial assembled them systematically and published the rationale alongside the results. Bradford Hill's later codification of these principles in his textbook and lectures, and in his 1965 criteria for causal inference, drew heavily on the practical experience of this trial.
Key People
- Austin Bradford Hill — Statistician and epidemiologist who designed the randomization methodology
- Philip D'Arcy Hart — MRC tuberculosis unit director who led the clinical implementation
- Selman Waksman — Microbiologist who isolated streptomycin at Rutgers in 1943
BMJ. 1948;2(4582):769-782
Related landmarks
- 1947 · The Nuremberg Code (Research Methods & Ethics)
- 1962 · Kefauver-Harris Drug Amendments (Research Methods & Ethics)
- 1964 · Declaration of Helsinki (Research Methods & Ethics)
- 1972 · Cochrane, 'Effectiveness and Efficiency' (Research Methods & Ethics)