tuberculosis (MDR TB) is estimated to kill about 150,000 people worldwide each
year. In the U.S. and some other developed countries, prescribing a variety of
antibiotics, instead of ones to which patients may be resistant, has greatly
reduced the number of cases of MDR TB. Researchers have long searched for a new
drug to more successfully treat this serious, life-threatening disease. One
drug developed by Johnson & Johnson, bedaquiline (SIRTURO), seemed to have
some promise in that relative to other drugs used to help patients with MDR TB,
it appeared to more rapidly result in patients’ sputum no longer containing the
tuberculosis (TB) bacteria (also known as sputum conversion).
In a clinical trial, patients with MDR TB who were already using other possibly
beneficial TB drugs were randomized into two groups. One group kept taking the
previous drugs and, in addition, was given a placebo. The other group kept using
their previous drugs but was given bedaquiline instead of a placebo.
At the end of 24 weeks, 79 percent of the group getting bedaquiline had
converted to negative sputum compared to 58 percent of the group getting a
placebo. So far, so good. In the absence of some downside to the drug, the
so-called surrogate marker, or biological measure used to indicate the effect
of treatment — in this case, sputum conversion — could result in actually
curing the patients’ disease, an important clinical outcome.
Unfortunately, a significant downside did exist. When the results were analyzed
three years after the start of the study, there were 10 deaths in the group of
79 patients randomized to get
bedaquiline, compared with two in
the group of 81 getting the placebo. This increased death rate was highly
In their enthusiasm to approve a drug for MDR TB, the FDA and its advisory
committee seem to have overlooked the significance of the increased deaths and,
over Public Citizen’s objections, the
drug was approved at the end of 2012.
Tragically, the FDA thought it could simply remedy
regulatory error of approving the drug by including the following text in the
Patient Medication Guide that will be distributed to those getting the drug:
“In one clinical trial, more deaths were seen in people who were treated with
SIRTURO compared to people who did not receive SIRTURO.”
We urgently need to be able to expect more than this from the FDA.
There is some controversy over the
approval for the
drug, as the FDA's ruling was based on a surrogate outcome (sputum cultures) as opposed to patient deaths. In the clinical
trials used for approval, the patients taking bedaquiline were more likely to
die, even though they had resolution of TB based on sputum cultures.
Adverse effects 
most common side effects of bedaquiline in studies were
nausea, joint and chest pain, and headache. The drug also has a black-box warningfor arrhythmias,
as it may induce long QT syndrome by blocking the hERG channel.
Problem with approving a drug based on surrogate marker.
Approval of a Tuberculosis Drug Based
on a Paradoxical Surrogate
Jerry Avorn, MD
have revealed several
problems with drugs evaluated on the basis of surrogate measure alone. Rosigliazone
(Avandai) was approved based on
its ability to reduce hemoglobin A1 levels in patients with diabetes. However,
8 yeas later the drug was found to
significantly increase the risk of myocardial infraction; it is now hardly ever
used. Ezetimibe (Vyytorin, Zetia) was
approved because it lowered low density lipoprotein cholesterol levels through
a novel mechanism; however, 10 yeas after approval the drug has not yet been
convincingly shown to reduce the risk of cardiac events. [Entails that patients
have not received an
effective treatment.] … However for
bedqauiline, the agency agreed that enrollment in that confirmatory trial [as required
by law] would not have to start until late 2013 or 2014 with study results not
required until 2022 [about the time it is likely to go off patent.]