Stephanie Fox-Rawlings, PhD, National Center for Health Research, June 6, 2019
Thank you for the opportunity to speak today on behalf of the National Center for Health Research. I am Dr. Stephanie Fox-Rawlings. Our Center analyzes scientific and medical data to provide objective health information to patients, health professionals, and policy makers. We do not accept funding from drug and medical device companies, so I have no conflicts of interest.
We can all agree that there is a need for new treatments for highly resistant TB that are more effective, safer, and easier to use. But the law and the mission of the FDA requires that new drugs be scientifically proven to work and have a well characterized safety profile before they are approved by the FDA. We don’t have that for pretomanid.
The clinical evidence provided for pretomanid combined it with two other drugs in one single-arm study. There is no randomized control group, so all we have are the results of a 3-drug regimen [bedaquiline, pretomanid, and linezolid]. That makes it impossible to scientifically determine pretomanid’s contribution to the patients’ outcomes.
To put this in historical context, the first US randomized clinical trial testing a new drug for TB was published in 1948, and it demonstrated that streptomycin was better than bed rest.1 The authors stated, “It had become obvious that, in future, conclusions regarding the clinical effect of a new chemotherapeutic agent in tuberculosis could be considered valid only if based on adequately controlled clinical trials.”
In other words, over 70 years ago clinicians and researchers understood that there were many factors that could affect the health impact of TB treatments, and that randomized, controlled studies were necessary to demonstrate that a specific treatment worked.
As recently as 2014, FDA argued for the need for randomized controlled clinical trials for new drugs to treat Ebola in an article in the New England Journal of Medicine.2 Despite the ebola crisis, the FDA authors stated that since the use of historical controls “cannot reliably identify effective treatments, their use could have tragic consequences. If historical comparisons falsely suggest a benefit or fail to detect modest but meaningful clinical effectiveness, the investigational drug might be erroneously adopted as effective or discarded as ineffective.”
FDA and industry have agreed on the need for an internal control group. For example. the ICH-E10- Choice of Control Group in Clinical Trials states, “Inability to control bias is the major and well-recognized limitation of externally controlled trials and is sufficient in many cases to make the design unsuitable. It is always difficult, and in many cases impossible, to establish comparability of the treatment and control groups and thus to fulfill the major purpose of a control group. The groups can be dissimilar with respect to a wide range of factors, other than use of the study treatment, that could affect outcome, … Such dissimilarities can include important but unrecognized prognostic factors that have not been measured.”3
Patients in the NIX-TB trial were compared to similar patients previously treated at one of the same clinics used in the trial to try to demonstrate that this drug combination was superior to combinations without any of these drugs. These patients were treated with typical care. If they had been enrolled in the trial and randomized to treatment, we might know if this drug combination led to better outcomes for patients or not.
It is important to note that bedaquiline was approved for MDR TB based on a trial that had a success rate of 78% when it was added to older drugs, which was significantly better than the success rate of the older drugs combined with placebo. However, this bedaquiline trial also reported more deaths in the bedaquiline group. This possible increased risk would not have been found without a comparator group.
This increased risk for death also highlights the problem of the surrogate endpoint — sputum cultures. Unless sputum cultures can predict survival or other endpoints that are meaningful to patients, they should not be used to justify FDA approval.
In summary, while new treatments are needed, it is impossible to accurately determine the risks or benefits of a new TB treatment without a randomized trial or a matched control group within the same trial. As clinicians and patients, you deserve to know the benefits and risks before deciding which treatments to use. This information is needed before approval, not years later.
- STREPTOMYCIN treatment of pulmonary tuberculosis. British Medical Journal. 1948;2(4582):769–782. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2091872/
- Cox E, Borio L, Temple R. Evaluating ebola therapies — The case for RCTs. New England Journal of Medicine. 2014;371:2350-2351. https://www.nejm.org/doi/full/10.1056/NEJMp1414145
- International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH harmonised tripartite guideline: Choice of control group and related issues in clinical trials E10. 2000. https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E10/Step4/E10_Guideline.pdf
The Antimicrobial Drugs Advisory Committee voted 14 to 4 in favor of approval in combination with bedaquiline and linezolid for adults with pulmonary extensively drug resistant (XDR) or treatment-intolerant or nonresponsive multidrug-resistant (MDR) tuberculosis. The drug was approved in August 2019.