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Statement on Bedaquiline to the FDA

Statement of Mark Harrington
Executive Director, Treatment Action Group
to the FDA Anti-Infective Drugs Advisory Committee (AIDAC) Hearing on the Use of Bedaquiline (TMC207) for Treatment of Multidrug-Resistant (MDR) Tuberculosis (TB)

Wednesday, November 28, 2012
Doubletree Hotel. Silver Spring, MD

I would like to thank the FDA and the committee chair for allowing Treatment Action Group (TAG) to deliver these remarks, which are dedicated to Dave McNeeley, a courageous clinician who for years led the bedaquiline development team at Tibotec/Janssen, to his colleague Karel de Beule, who worked on BDQ but did not live to see this day, and finally to a courageous South African pediatrician, Dr. Dalene van Delft, who contracted MDR-TB as a result of her work at Stellenbosch University, developed serious hearing loss from the injectable, and was cured as a result of being one of only four South Africans able to obtain bedaquiline on compassionate use.

Though I have been attending FDA hearings since 1989, in a period that has seen FDA approval of over 30 drugs to treat HIV, and currently over 8 million people are receiving lifesaving HIV treatment all over the world, no new drug for TB has been reviewed by the FDA since 1970.

At current rates, TB will kill 14 million people in the next decade. Over 1 million people are living with MDR-TB, most of them never properly diagnosed, and with only about 5% of them even receiving appropriate treatment. In addition, fewer than half of those treated for MDR-TB experience successful treatment, and even when successful, cure may involve loss of hearing, psychosis, chemical hepatitis, neuropathy, and other drastic side effects.

1.      TAG, along with the Global TB Community Advisory Board (TB CAB), HIV i-Base, South Africa’s Treatment Action Campaign (TAC), Médecins Sans Frontières (MSF), and the Southern African HIV Clinicians’ Society, supports appropriate early access to bedaquiline for patients with drug-resistant TB, including multidrug-resistant (MDR) and extensively drug resistant (XDR) disease (

2.      TAG supports accelerated approval for bedaquiline based on the evidence presented here today by Janssen and in light of the FDA analysis.

3.      In addition TAG would support a traditional approval for bedaquiline based on the evidence presented here today in light of the FDA analysis with the stipulation that the recommended postmarketing studies take place. This recommendation is based on the fact that as far back as the 1972 publication by the East African/Medical Research Council, two-month sputum culture conversion (SCC) with the six-month short-course curative regimen of streptomycin, rifampin, and isoniazid successfully predicted relapse-free survival at the end of the study.[1]

In the randomized MRC study, 6SRH converted cultures faster than any other regimen (73% at 2m vs. 56% on standard of care), as measured by 2m conversion, was equally effective at 6m to SOC (96% vs. 98%), and came close to the 18m standard of care in relapse rates (4% vs. 2%), while cutting treatment time by 12 months.

For comparison, in Janssen study C208 stage 1, with a primary endpoint at week 8 time-to-culture conversion, 48% converted on BDQ + standard background regimen (BR) versus a paltry 9% on the standard background regimen. (Janssen Research & Development. Bedaquiline (TMC207) FDA Advisory Committee presentation. November 28, 2012.)

4.      Whether granting accelerated or traditional approval for bedaquiline, the FDA should stipulate that the sponsor conduct necessary and required postmarketing studies, including:

  • the pediatric studies mentioned by Dr. Christian Lienhardt of the World Health Organization (WHO);
  • cardiac studies of important potential drug-drug interactions such as with Otsuka’s delamanid (OPC-67683), the nitroimidazooxazole recently submitted for review by the European Medicines Agency (EMA);
  • drug-drug interaction studies with commonly used antiretroviral therapies such as atazanavir, darunavir, efavirenz, raltegravir, and other drugs likely to be used in combination by people with HIV and MDR-TB;
  • appropriate, rationally designed studies of optimal regimens to treat drug-sensitive TB (DS-TB), drug-resistant TB (DR-TB), and latent TB infection (LTBI); and
  • development of appropriate genotypic and phenotypic drug susceptibility and resistance surveillance (DST, DRS) tests to help guide practice and protect patients from the emergence of unnecessary drug resistance.

5.      The introduction of new drugs and regimens to treat TB offers the chance to revolutionize TB treatment, making all forms of TB curable more quickly, more safely, and more effectively, saving millions of lives and billions of dollars. If the FDA grants approval to bedaquiline today, it will provide a major incentive for new sponsors and companies to introduce more new drugs, classes, compounds, combinations, and regimens into the clinical pipeline. The FDA successfully pioneered accelerated approval for HIV treatment in 1991–92, and by 1996 we had gotten to highly effective antiretroviral therapy (HAART) with triple combination therapy and quantitative, real-time viral load as a validated surrogate marker. As noted previously, we now have over 30 FDA-approved HIV drugs, and 8 million people are alive today because of them.

6.      To navigate the changing landscape of TB diagnosis and treatment research and implementation over the coming decade, a new multi-stakeholder collaboration will be required, bringing together communities, people living with TB, activists, ethicists, developers, public-health authorities, domestic and global research and health agencies, implementers in high-burden countries, and researchers. While we have some emerging structures such as the Critical Path to TB Regimens (CPTR) initiative, we need a broader and much more global process to identify, manage, optimize, and rationalize the design, conduct, and implementation of successful new short-course regimens to cure all forms of TB, including DS- and DR-TB, LTBI, pediatric TB, and TB/HIV. One model for such a process would look like an adapted version of the Forum for Collaborative HIV Research (FCHR), which has periodically convened all U.S. stakeholders involved in HIV research since 1997, and which has helped to move forward the field on a sound, scientific-evidence base.

7.      You have the chance to make history today. Be bold. Make history. But do it stringently, and require the sponsor to carry out the necessary postmarketing studies to ensure that people with TB and their providers get the necessary information to make the best possible use of this first in a new generation of TB drugs.

You today have the power to usher in a renaissance of TB drug development. I hope you will seize the day.

[1] East African/British Medical Councils. Controlled clinical trial of short-course (6-month) regimens of chemotherapy for treatment of pulmonary tuberculosis. Lancet. 1972 May 20;1(7760):1079–85.


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