MRC Streptomycin Trial for Pulmonary Tuberculosis

In 1947 the established treatment for pulmonary tuberculosis in Britain was bed rest in a sanatorium, sometimes supplemented by surgical collapse of a diseased lung. Streptomycin had been isolated by Albert Schatz in Selman Waksman's laboratory at Rutgers in 1943 and was active against Mycobacterium tuberculosis. The question of whether it worked in patients was urgent, but supplies were limited: in 1946 the British government bought 50 kilograms from the United States, far too little to treat everyone who might benefit. That scarcity made a controlled allocation ethically defensible and practically necessary.

Austin Bradford Hill, the statistician on the trial, had seen how an unconcealed allocation schedule weakened an earlier MRC trial of serum treatment for pneumonia. For streptomycin he used sealed envelopes, prepared from random number tables and opened only after a patient had been admitted to the trial. This concealment prevented clinicians from influencing which patients entered each arm. The trial enrolled 107 patients with acute progressive bilateral pulmonary tuberculosis at several British centers: 55 were allocated to streptomycin plus bed rest, 52 to bed rest alone.

At six months, 4 of the 55 streptomycin patients (7 percent) had died, compared with 14 of the 52 controls (27 percent). Radiographic assessments were made independently by two radiologists and a clinician, each unaware of the patient's treatment assignment. The results appeared in the BMJ on October 30, 1948. The report urged caution all the same: no patient had been cured, some controls improved markedly on bed rest alone, and streptomycin could damage the inner ear.

The trial also documented drug resistance: tubercle bacilli in many streptomycin-treated patients soon became resistant. Philip D'Arcy Hart, secretary of the MRC's streptomycin trials committee, and Hill saw that resistance would limit single-drug treatment. A second MRC trial, begun in 1948, compared streptomycin, para-aminosalicylic acid (PAS) and the two combined, and the combination was in routine use in Britain by the end of 1951. Isoniazid, found early in 1952 to act against tuberculosis, was then added to combined regimens.

The trial was run by a small team: D'Arcy Hart, Hill, the field coordinator Marc Daniels and the administrator Charlene Agnew. The James Lind Library, which documents the history of fair tests of treatments, singles out the 1948 report for describing in detail the steps taken to keep investigators from knowing the next treatment assignment.