Diapositiva 1 - The European Respiratory Society
Download
Report
Transcript Diapositiva 1 - The European Respiratory Society
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
Trial organization
Constraints related to TB-MDR trials
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
Agenda
Trial organization
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 :
Initial design and protocol development
Ethics Committee review
Patients recruitment sites
Treatment phase
Follow-up phase
Data analysis
Publication of the results
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
Site requirements-1
Sites with patients !
A stable population
Common protocol
Drug supplies
Costs (indirect and direct)
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
Data management
Data entry
Data analysis
Statistical analysis (The results should not drive the
analysis. Objectives are decided before the results
are obtained)
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
Agenda
Trial organization
Constraints related to TB-MDR trials
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
Common constraints of clinical trials
Methodological issues
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……….
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.)
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)
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
Try to plan a clinical trial on a new anti-TB
drug……….
Trial justification
Trial objectives
Treatment schedules
Trial endpoint:
Statistical approach
Publication agrrement
And thank you to: