CDC History of Tuberculosis Control - Medical and Public Health ...

The First TB Drug Clinical Trials
by Rick O’Brien, MD
Chief, Research and Evaluation Branch, DTBE
and George Comstock, MD, DrPH, FACE
Alumni Centennial Professor of Epidemiology
Johns Hopkins University
School of Hygiene and Public Health
The United States Public Health Service
(USPHS), together with the British Medical
Research Council (MRC) and the US Armed
Forces–Veterans Administration Cooperative
Trials, played a key role in the development of
the chemotherapy of TB.
The first USPHS trial, a placebo-controlled
study of streptomycin, was initiated by the
Field Studies Section and the Tuberculosis
Study Section of the National Institutes of
Health (NIH) in 1947, the same year as the
much smaller but better known MRC study of
streptomycin. In the PHS study, a total of 541
patients with moderate to far-advanced pulmonary
TB were enrolled at 14 hospitals and
sanatoria throughout the US and Alaska. The
published account gives no hint of how this
controlled evaluation of streptomycin was
saved from being only the series of uncontrolled
observations
that was initially
proposed. Funds for
a study of streptomycin
in the treatment
of TB had been
allocated, probably
in 1946, to a number
of prominent hospitals.
When Carroll
Palmer heard that
there were to be no
controls, he was
upset and expressed
his concerns to Dr. Van Slyke, director of the
NIH. Van Slyke agreed with Palmer, and
directed that a controlled trial be planned and
conducted under the general supervision of the
newly convened Tuberculosis Study Section.
Dr. Esmond Long, from Phipps Clinic in
Notable Events in TB Control
51
Philadelphia, was the chairman of the Study
Section’s Steering Committee. Ms. Ferebee,
Chief of the Therapy Evaluation Branch, Field
Studies Section, became the study administrator.
With some grumbling from those who
had lost their streptomycin allocation, a
controlled trial was conducted, although
without the placebo controls Palmer and
Ferebee had wished. All investigators took
part in various reviews of clinical and radiographic
findings and in committees set up to
consider appeals from the protocol, procedures
continued in future PHS therapy trials
as a way to bring investigators together and
give them a real part in major decisions.
The study demonstrated the remarkable
ability of streptomycin to reduce mortality
and improve clinical status. However,
monotherapy with streptomycin led to the
development of drug resistance in a significant
number of patients. In 1951, the one-year
status was reported for the patients given
streptomycin: 40% had negative cultures, 5%
had died, 17% still had tubercle bacilli sensitive
to streptomycin, and 39% had resistant
organisms. In another 1951 report, PAS was
found to be highly effective in preventing
resistance to dihydrostreptomycin (similar in
action to streptomycin but with a higher risk
of ototoxicity.)
The second USPHS study, begun in 1949 at 11
institutions, randomized a total of 315 patients
to either streptomycin or streptomycin-PAS.
After 6 months of treatment, over 40% of
patients receiving monotherapy developed
streptomycin resistance, compared to only
12% of patients on combination therapy.
A major advance in TB treatment occurred in
1952 with the initial report of an MRC study
of isoniazid. During the next 2 years, a total of
5,324 patients were enrolled in three USPHS
trials (which became known as Studies 1, 2,
and 3), examining a variety of combinations of
the three drugs. The conclusion of these
studies was that the triple combination did not