Thank you for the opportunity to speak today on behalf of the National Research Center for Women and Families. Our nonprofit research center does not accept funding from pharmaceutical companies, so I have no conflicts of interest.
I am Dr. Jennifer Yttri, and I have a doctorate in immunology from Washington University. I agree that the options for treatment of multi-drug resistant tuberculosis are few. New antibiotics are needed.
The FDA has the responsibility to approve drugs that will protect those who are most vulnerable and have the greatest need: the sickest patients. Safety and efficacy should not be sacrificed when approving new drugs.
Unfortunately, the data on bedaquiline indicate that the benefit to patients with multi drug resistant tuberculosis is questionable. We applaud Janssen for conducting scientifically sound, double blind, superiority trials in the population for which the drug is intended: an international group of patients with multi drug resistant TB. This is the kind of study that the FDA should rely on, with clear conclusions coming from the data. Unfortunately, the results show that adding bedaquiline to the current standard of care does not benefit the target population. If you recommend approval for bedaquiline, it is very likely that more patients will be harmed than helped.
TB is not a short term disease. It persists after an initial clearance and can recur even 300 days later. That is why long-term data are absolutely essential to assess the benefits of antibiotic treatment.
More data needs to be collected past the 24 week treatment phase. Although bedaquiline may have a positive short-term effect in limiting mycobacterial growth, the long-term data thus far indicate that the early benefits do not last and are replaced by increased rates of death.
The initial long term data indicate the chances of a patient dying were HIGHER with the addition of bedaquiline than with the standard antibiotic cocktail. The contribution of bedaquiline or its metabolytes cannot be ruled out. Look at the survival data, there is not one point in time where I would choose to use bedaquiline in addition to other available treatments. I would not choose it for myself or for anyone I care about. Would you?
Bedaquiline was tested using time to sputum culture conversion. In simple terms, this test determines when and if mycobacteria are prevented from growing. It is a test used by doctors to track the development of TB, but doesn’t say anything about patient survival, which is what we all are concerned about. In fact, a series of studies published in the past month suggest that sputum culture conversion is not a good predictor of clinical outcome in MDR-TB patients.
Instead of using a surrogate endpoint, like sputum culture, the FDA should rely on patient centered outcomes, like mortality rate. In the first clinical study of an antibiotic treatment in 1948, killing TB bacteria wasn’t the important measurement. Instead, streptomycin was shown to increase patient survival. Now, we consider drugs like bedaquiline that increase mortality by 10% and attempt to rationalize the death as a consequence of the disease we want to treat or unrelated causes. We should require drugs to decrease mortality and improve disease.
There are very clear dangers in using surrogate endpoints to predict future benefit. Approval of drugs based on the promise of benefit is a dangerous practice. Consider the case of Avastin, which was approved by FDA for metastic breast cancer based on its ability to slow tumor progression. After years on the market, and billions of dollars spent, it was finally clear that patients taking Avastin survived for a shorter time, with a worse quality of life, than patients who took placebo. When the FDA attempted to revoke approval, they were met with delaying tactics and hostility, despite the clear evidence.
The FDA’s responsibility is to approve drugs that will help, not harm, consumers. Treatments exist for patients with multi drug resistant TB that are safer without the addition of bedaquiline. Please do the right thing for patients by sending the clear message to the FDA that we expect new medications to “do no harm” compared to existing treatments.
The FDA is a scientific agency and I hope you will ask the agency to make its decisions based on science, not wishful thinking.
For more comments on bedaquiline see our article in Health Affairs.