Elsevier

Tuberculosis

Volume 88, Supplement 1, August 2008, Pages S85-S92
Tuberculosis

Design issues in pivotal drug trials for drug sensitive tuberculosis (TB)

https://doi.org/10.1016/S1472-9792(08)70039-8Get rights and content

Summary

The urgent need for new anti-tuberculosis drugs raises the question of the design, conduct and analysis of the trials that will be required for licensing purposes. Current standard regimens are highly effective under controlled trial conditions with relapse rates of 5% or less. It is very unlikely better results can be achieved with new drugs, a clinically more relevant goal would be a regimen of comparable efficacy to standard treatment but of substantially shorter duration. In order for a new regimen to be licensed, it will be necessary to demonstrate that it is of comparable efficacy to the standard regimen. An important issue will be the choice of the margin of non-inferiority which needs to be justified both on statistical and clinical grounds; non-inferiority could be falsely concluded if a trial was not conducted appropriately, with substantial losses to follow-up or unsatisfactory laboratory procedures. It is particularly important therefore that such trials are conducted with a high degree of rigor. Analyses should be performed both by intention to treat, which is conservative and therefore biased towards no difference, and on a protocol correct population. Similar conclusions would be required from both analyses. Substantial developments have been made in tuberculosis bacteriology in recent years enhancing our ability to diagnose and differentiate strains of M. tuberculosis. Many of these techniques affect the design of trials but have yet to be evaluated in that setting. Non-inferiority pivotal trials require that, as far as practicable, the same techniques are used as were employed when the trials assessing the standard regimen were conducted.

References (26)

  • A Jindani et al.

    Two 8-month regimens of chemotherapy for treatment of newly diagnosed pulmonary tuberculosis: international multicentre randomized trial?

    Lancet

    (2004)
  • W Fox

    Whither Short Course Chemotherapy?

    Br J Dis Chest

    (1981)
  • S Garattini et al.

    Non-inferiority trials are unethical because they disregard patients' interests?

    Lancet

    (2007)
  • AJ Nunn et al.

    The ethics of non-inferiority trials?

    Lancet

    (2008)
  • Tuberculosis in Kenya: follow-up of the second (1974) national sampling survey and a comparison with the follow-up data from the first (1964) national sampling survey. An East African and British Medical Research Council co-operative investigation?

    Tubercle

    (1979)
  • East African/British Medical Research Council

    Controlled clinical trial of four short course (6 month) regimens of chemotherapy for treatment of pulmonary tuberculosis. Third report?

    Lancet

    (1974)
  • Committee for Medicinal Products for human use: Guideline on the choice of the non-inferiority margin

    CPMP

    (2005)
  • East African/British Medical Research Council

    Controlled clinical trial of four short course (6 month) regimens of chemotherapy for treatment of pulmonary tuberculosis?

    Lancet

    (1973)
  • East African/British Medical Research Council

    Controlled clinical trial of five short course (4-month) chemotherapy regimens in pulmonary tuberculosis. Second report of the 4th study?

    Am Rev Respir Dis

    (1981)
  • Singapore Tuberculosis Service/British Medical Research Council

    Clinical trial of six-month and four-month regimens of chemotherapy in the treatment of pulmonary tuberculosis: The results up to 30 months?

    Tubercle

    (1981)
  • International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use....
  • W Fox et al.

    Studies on the treatment of tuberculosis undertaken by the British Medical Research Council Tuberculosis Units, 1946–1986, with relevant subsequent publications

    Int J Tuberc Lung Dis

    (1999)
  • East African and Central African/British Medical Research Council

    Controlled clinical trial of 4 short course regimens of chemotherapy (three 6-month and one 8-month) for pulmonary tuberculosis. Final report?

    Tubercle,

    (1986)
  • Cited by (36)

    • High-dose rifapentine with or without moxifloxacin for shortening treatment of pulmonary tuberculosis: Study protocol for TBTC study 31/ACTG A5349 phase 3 clinical trial

      2020, Contemporary Clinical Trials
      Citation Excerpt :

      For the current study, the 6.6% margin of non-inferiority preserves >50% of the above 19.3% M1 estimate. Considering the clinical argument [58,59], the investigators for the current study, in broader consultation within the two large publicly-funded international consortia of TB stakeholders that participate in the current study (CDC TB Trials Consortium and NIH AIDS Clinical Trials Group), consider the benefits of a shortened rifapentine-based regimen to justify the margin of 6.6%. Study investigators consider 600 patients per arm sufficiently large to provide adequate precision on the difference in efficacy between the regimens to determine whether an intervention regimen might be considered not inferior to the control regimen.

    • New antituberculosis drugs, regimens, and adjunct therapies: Needs, advances, and future prospects

      2014, The Lancet Infectious Diseases
      Citation Excerpt :

      If results are promising, this combination might lead to the development of a phase 3 pivotal trial. The novel multiarm multistage (MAMS) trial design compares several regimens simultaneously.78–80 Planned interim analyses act as intermediate checkpoints and are used to compare the experimental groups with common controls.

    • Moxifloxacin for tuberculosis

      2012, The Lancet Infectious Diseases
    • Noninferiority Trials

      2022, Principles and Practice of Clinical Trials
    View all citing articles on Scopus
    View full text