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
Agenda
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Trial organization
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Constraints related to TB-MDR trials
Need for novel TB drugs and regimens
Need for novel TB drugs and regimens that would:
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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
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Harmonization (ICH) Good Clinical Practice (GCP) and
Good Laboratory Practice (GLP) standards
Agenda
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Trial organization
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Constraints related to TB-MDR trials
Organization of a trial
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
IV
Disease people
Efficacy of the drug,
tolerability, safety
Post-marketing
Conduct of clinical trials
A well conducted clinical trial must follow well defined
steps in order to arrive at a valid result. These are :
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Initial design and protocol development
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Ethics Committee review
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Patients recruitment sites
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Treatment phase
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Follow-up phase
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Data analysis
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Publication of the results
Section of the protocol. Initial design.
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Background and aims
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Specific objectives
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Trial design
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Eligibility criteria (including those ineligible)
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Trial endpoints (primary and secondary)
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Randomization procedure [sample, stratified, at cluster, systematic, at presentation]
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Treatment/intervention details (drug: dose, posology)
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Assessment of endpoints
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Follow-up procedures (physical examination, culture tests, blood tests)
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Statistical considerations including outline of analysis plan (comparative, equivalence; type
of the statistical analysis: interim analysis for safety reasons)
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Procedure for handling adverse events, in particular serious adverse events
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Committee membership
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Appendices, including patient information sheet and consent form, tables with outlines of
the protocol
Site requirements-1
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Sites with patients !
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A stable population
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Common protocol
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Drug supplies
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Costs (indirect and direct)
Site requirements-2
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Organizational structure (outpatient service)
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Standardization
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Monitoring
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Mycobacteriology laboratory of high quality
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Facility for HIV testing and counseling
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Computing facilities
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Good Clinical Practice
Data management
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Data entry
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Data analysis
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Statistical analysis (The results should not drive the
analysis. Objectives are decided before the results
are obtained)
The rôle of the Central Coordinating Office
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Overseeing the development of the protocol
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Recruitment of the participating centres
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Training of the local staff
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Despatch of the drugs and study forms to the participating centres
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Randomisation
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Monitoring the conduct of the study
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Data management
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Site visits
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Organising the meetings of the Steering Committee
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Organising the meetings of the Data and Safety Monitoring Committee
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Dissemination of results
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Obtaining funds for each trial
Agenda
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Trial organization
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Constraints related to TB-MDR trials
Constraints of clinical trials for MDR-TB
compared to trails for TB
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To generate homogeneous cohorts of patients with
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similar drug resistance
using identical drugs
main confounding variables (gender, age, co-morbidities,
etc.)
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Severe clinical conditions
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Longer duration of treatment
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Drug toxicity more frequent per se and if concomitant HIV
disease
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Drug-drug interactions (anti-TB and/or anti-HIV drugs)
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Sample size
Common constraints of clinical trials
Methodological issues
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Homogenous clinical management among the
different sites
Homogenous diagnostic work-up among the different
sites
Drug shortages
Try to plan a clinical trial on a new anti-TB
drug……….
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Trial justification. Ex: TB needs better treatment….
Trial objectives. Ex: shorten time of therapy , i.e. 4
months vs 6 months
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Treatment schedules. Ex: write the proposed schedule
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Trial endpoint:
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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.)
Try to plan a clinical trial on a new anti-TB
drug……….
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Statistical approach
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New regimen better than standard therapy
New regimen equivalent than standard therapy
Other…
Publication (agreement on the PI, etc)
Critical Path to New TB Regimens (CPTR)
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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
Try to plan a clinical trial on a new anti-TB
drug……….
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Trial justification
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Trial objectives
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Treatment schedules
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Trial endpoint:
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Statistical approach
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Publication agrrement
And thank you to: