Harming Tuberculosis Patients Instead of Helping Them?

Multiple drug-resistant 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 statistically significant.

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 this serious 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.