Diapositiva 1

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National Institute for Infectious Diseases L.
Spallanzani Roma, Italy

• Constrains and common mistakes
  in TB/MDR TB clinical trials
• Delia Goletti and Giovanni Sotgiu
• Borstel, May 28th, 2010

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Agenda

• Trial organization
• Constraints related to TB-MDR trials

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Need for novel TB drugs and regimens

• Need for novel TB drugs and regimens that would
• Time, shorten current treatment duration and/or
  allow more widely spaced intermittent treatment
• Amount of pills (10 or more at the moment)
• Avoid parental injection
• Safety and drug interaction especially in TB-HIV
  patients concurrently being treated for HIV
  infection
• TB drug trials have to be conducted to
  registration standards compliant with the
  International Conference on
• Harmonization (ICH) Good Clinical Practice (GCP)
  and
• Good Laboratory Practice (GLP) standards

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Agenda

• Trial organization
• Constraints related to TB-MDR trials

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Organization of a trial
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Phases of the clinical trials
Phase Subjects enrolled Objective
I Healthy donors Safety
IIA Disease people Efficacy of the drug
IIB Disease people Dosage
III Disease people Control group. Ex disease people under gold standard therapy placebo Efficacy of the drug, tolerability, safety
IV Disease people Post-marketing
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Conduct of clinical trials

• A well conducted clinical trial must follow well
  defined steps in order to arrive at a valid
  result. These are
• Initial design and protocol development
• Ethics Committee review
• Patients recruitment sites
• Treatment phase
• Follow-up phase
• Data analysis
• Publication of the results

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Section of the protocol. Initial design.

• Background and aims
• Specific objectives
• Trial design
• Eligibility criteria (including those
  ineligible)
• Trial endpoints (primary and secondary)
• Randomization procedure sample, stratified, at
  cluster, systematic, at presentation
• Treatment/intervention details (drug dose,
  posology)
• Assessment of endpoints
• Follow-up procedures (physical examination,
  culture tests, blood tests)
• Statistical considerations including outline of
  analysis plan (comparative, equivalence type of
  the statistical analysis interim analysis for
  safety reasons)
• Procedure for handling adverse events, in
  particular serious adverse events
• Committee membership
• Appendices, including patient information sheet
  and consent form, tables with outlines of the
  protocol

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Site requirements-1

• Sites with patients !
• A stable population
• Common protocol
• Drug supplies
• Costs (indirect and direct)

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Site requirements-2

• Organizational structure (outpatient service)
• Standardization
• Monitoring
• Mycobacteriology laboratory of high quality
• Facility for HIV testing and counseling
• Computing facilities
• Good Clinical Practice

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Data management

• Data entry
• Data analysis
• Statistical analysis (The results should not
  drive the analysis. Objectives are decided before
  the results are obtained)

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The rôle of the Central Coordinating Office

• Overseeing the development of the protocol
• Recruitment of the participating centres
• Training of the local staff
• Despatch of the drugs and study forms to the
  participating centres
• Randomisation
• Monitoring the conduct of the study
• Data management
• Site visits
• Organising the meetings of the Steering Committee
• Organising the meetings of the Data and Safety
  Monitoring Committee
• Dissemination of results
• Obtaining funds for each trial

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Agenda

• Trial organization
• Constraints related to TB-MDR trials

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Constraints of clinical trials for MDR-TB
compared to trails for TB

• To generate homogeneous cohorts of patients with
• similar drug resistance
• using identical drugs
• main confounding variables (gender, age,
  co-morbidities, etc.)
• Severe clinical conditions
• Longer duration of treatment
• Drug toxicity more frequent per se and if
  concomitant HIV disease
• Drug-drug interactions (anti-TB and/or anti-HIV
  drugs)
• Sample size

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Common constraints of clinical trials

• Methodological issues
• Homogenous clinical management among the
  different sites
• Homogenous diagnostic work-up among the different
  sites
• Drug shortages

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Try to plan a clinical trial on a new anti-TB
drug.

• Trial justification. Ex TB needs better
  treatment.
• Trial objectives. Ex shorten time of therapy ,
  i.e. 4 months vs 6 months
• Treatment schedules. Ex write the proposed
  schedule
• Trial endpoint
• culture conversion rate, or other surrogate
  markers
• relapse rate (define the period within a year, 2
  years..) ,
• time to death,
• changes in radiographic extent of disease and
  cavitation,
• urine tests for compliance,
• adverse events (stop the trial, etc.)

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Try to plan a clinical trial on a new anti-TB
drug.

• Statistical approach
• New regimen better than standard therapy
• New regimen equivalent than standard therapy
• Other
• Publication (agreement on the PI, etc)

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Critical Path to New TB Regimens (CPTR)

• In March 2010 was launched
• Objective to promote the development of new
  regulatory approaches that support innovative
  research into TB therapeutics and evaluate the
  safety and efficacy of new TB drugs combination
• Ex to test regimens that include more than one
  experimental compound at a time, shifting the
  unit of development from individual TB drugs to
  entire regimens
• They are going to test 9-10 new TB drug regimens
  starting next year

Spigelman et al, IJTLD June 2010
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Try to plan a clinical trial on a new anti-TB
drug.

• Trial justification
• Trial objectives
• Treatment schedules
• Trial endpoint
• Statistical approach
• Publication agrrement

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And thank you to