Upload
national-press-foundation
View
225
Download
0
Embed Size (px)
Citation preview
8/7/2019 Clinical Trials (Mauro Schechter)
http://slidepdf.com/reader/full/clinical-trials-mauro-schechter 1/33
Projeto Praça OnzeUniversidade Federal do Rio de Janeiro
Clinical Trials at AIDS Vaccine µ09
Scientific Journalists Training Program
Global HIV Vaccine Enterprise
Paris, October 19, 2009
Mauro Schechter Principal Investigator, Projeto Praça Onze
Professor of Infectious DiseasesUniversidade Federal do Rio de Janeiro
8/7/2019 Clinical Trials (Mauro Schechter)
http://slidepdf.com/reader/full/clinical-trials-mauro-schechter 2/33
Development of HIV vaccines
Laboratory and animal protection
experiments
20±50 HIV-negative volunteers (lower risk);safety and immunogenicity
I I
II II
III III IV IV
100s of HIV-negative volunteers (lower and higher risk); safety, immunogenicity; doses, routes of administration, different populations
1000s of HIV-negative volunteers (higher risk);
efficacy
Effectiveness; operational research
Pre-clinical phase
Clinical
Phases
*
*
* Randomized clinical trials
8/7/2019 Clinical Trials (Mauro Schechter)
http://slidepdf.com/reader/full/clinical-trials-mauro-schechter 3/33
Randomised Controlled Trials (RCTs)
� Experimental, (usually) longitudinal, prospective
� R andomised ± ensures that treatment groups aresimilar at start of trial; any differences are due to
chance only
� Controlled ± control group allows to conclude thatoutcome is due to the test vaccine rather than someother factor
� Comparison is usually between a new regimen orintervention and an existing standard of care orplacebo
8/7/2019 Clinical Trials (Mauro Schechter)
http://slidepdf.com/reader/full/clinical-trials-mauro-schechter 4/33
Generalisability
� Participants can be different from those that will use the vaccine
� Eligibility criteria often leads to groups of patients being excluded
(e.g. STI co-infection)
Length of trial and primary endpoints
� Typically 1-3 years long, thus efficacy of over the longer-term is not
assessed
� Surrogate markers versus clinical events
Limitations of randomized
clinical trials
8/7/2019 Clinical Trials (Mauro Schechter)
http://slidepdf.com/reader/full/clinical-trials-mauro-schechter 5/33
Follow-up of patients
� Participants are generally seen more regularly and followed more
intensely than in routine practice - this may influence behaviour, etc.
� Feasibility
� Potential participants may not want to leave an important decision
up to chance
� Rare events are difficult to assess in RCTs as long follow-up periods
and large numbers of patients are required
� Ethics
� It may be unethical to withhold an intervention to form a controlgroup
Limitations of randomized
clinical trials
8/7/2019 Clinical Trials (Mauro Schechter)
http://slidepdf.com/reader/full/clinical-trials-mauro-schechter 6/33
Practical aspects of clinical trials
� Question being studied
� Trial population/Control group
� Trial design� Analysis (pre-specified vs. post-hoc)
8/7/2019 Clinical Trials (Mauro Schechter)
http://slidepdf.com/reader/full/clinical-trials-mauro-schechter 7/33
Practical aspects of clinical trials
� Question being studied
� Trial population/Control group
� Trial design� Analysis (pre-specified vs. post-hoc)
8/7/2019 Clinical Trials (Mauro Schechter)
http://slidepdf.com/reader/full/clinical-trials-mauro-schechter 8/33
Practical aspects of clinical trials
� Question being studied
� Trial population/Control group
� Trial design� Analysis (pre-specified vs. post-hoc)
8/7/2019 Clinical Trials (Mauro Schechter)
http://slidepdf.com/reader/full/clinical-trials-mauro-schechter 9/33
Trial populations
� Explicit and objective inclusion and exclusion criteriaare required for any R CT
� Narrow and restrictive inclusion criteria can allow to
focus on a specific group of people and reducevariability in the outcome
� However, included participants may not berepresentative of those who may receive the vaccine inthe future
8/7/2019 Clinical Trials (Mauro Schechter)
http://slidepdf.com/reader/full/clinical-trials-mauro-schechter 10/33
The need for a control group
� µHawthorn effect¶: observation that patients in clinicaltrials generally do better than similar patients on sametreatment (closer monitoring, clear treatment plan,enthusiastic team, etc.)
� Therefore, a control group provides the opportunity tosee µwhat would have happened without the newintervention¶
8/7/2019 Clinical Trials (Mauro Schechter)
http://slidepdf.com/reader/full/clinical-trials-mauro-schechter 11/33
The need for randomisation
� Patient allocation to new intervention or controlgroups is determined purely by chance
� Thus, any differences between the different arms of
the trial are due to chance alone
� This includes both known and unknown factors
� Thus, provided individuals are treated similarly duringthe study period, any differences in outcome between
the two groups can be attributed to the intervention
8/7/2019 Clinical Trials (Mauro Schechter)
http://slidepdf.com/reader/full/clinical-trials-mauro-schechter 12/33
Practical aspects of clinical trials
� Question being studied
� Trial population/Control group
� Trial design� Analysis (pre-specified vs. post-hoc)
8/7/2019 Clinical Trials (Mauro Schechter)
http://slidepdf.com/reader/full/clinical-trials-mauro-schechter 13/33
Blinding
� Bias can occur if a patient or treatment team are awareof treatment allocation
� Patient: psychological effect on behaviour
� Clinical team: intensity of counselling
8/7/2019 Clinical Trials (Mauro Schechter)
http://slidepdf.com/reader/full/clinical-trials-mauro-schechter 14/33
Types of RCTs
� Parallel group: each patient is randomised to receiveonly one of the two different strategies
� Crossover trial: each patient receives first one
treatment strategy then the other, but the treatmentorder is randomised
� Cluster randomised: each µcluster¶ of patients(hospitals, outpatient clinics) randomised to receiveone of the two different treatment strategies
8/7/2019 Clinical Trials (Mauro Schechter)
http://slidepdf.com/reader/full/clinical-trials-mauro-schechter 15/33
Parallel design trials
Randomisation
New intervention
Control group
Present time
Comparetreatment
groups
Follow individuals
Starting point
8/7/2019 Clinical Trials (Mauro Schechter)
http://slidepdf.com/reader/full/clinical-trials-mauro-schechter 16/33
Cross-over trials
Randomisation
New Intervention
Control group
Present time Future timeFollow individuals
Starting point
New Intervention
Control group
Wash out
8/7/2019 Clinical Trials (Mauro Schechter)
http://slidepdf.com/reader/full/clinical-trials-mauro-schechter 17/33
Crossover trial
� Crossover trials are particularly useful for short termoutcomes in chronic conditions
� The treatment must be one that does not permanently
alter the disease or condition under study
� The main limitation of a crossover trial is that theeffect of the first treatment administered may carryover and alter subsequent responses
8/7/2019 Clinical Trials (Mauro Schechter)
http://slidepdf.com/reader/full/clinical-trials-mauro-schechter 18/33
Cluster randomised trials
Randomisation of
Hospital/Clinic
New Intervention
All patients at
hospital/clinic
receive new
intervention
All patients at
hospital/clinic
receive new
intervention
Control group
8/7/2019 Clinical Trials (Mauro Schechter)
http://slidepdf.com/reader/full/clinical-trials-mauro-schechter 19/33
Clinical Trials at AIDS Vaccine µ09
8/7/2019 Clinical Trials (Mauro Schechter)
http://slidepdf.com/reader/full/clinical-trials-mauro-schechter 20/33
SS01-02Clinical outcomes from the STEP study
Background
� 3,000 men and women
� 3 doses of MRKAd5 gag/pol/nef vaccine or placebo� Vaccinations stopped after a pre-specified interim analysis
in Ad5 seronegative participants demonstrated no
protective effect on HIV acquisition or early plasma viral
load� Further analysis demonstrated an increased hazard ratio
(HR) for HIV acquisition among Ad5 seropositive and
uncircumcised vaccinees vs. placebo recipients
8/7/2019 Clinical Trials (Mauro Schechter)
http://slidepdf.com/reader/full/clinical-trials-mauro-schechter 21/33
SS01-02Clinical outcomes from the STEP study
Objective
� To compare rates of HIV acquisition among vaccine vs.placebo recipients
Methods
� Pre-unblinding data were frozen as of Oct 17, 2007;
� Post-unblinding data are from Oct 18, 2007 through
January 23, 2009
8/7/2019 Clinical Trials (Mauro Schechter)
http://slidepdf.com/reader/full/clinical-trials-mauro-schechter 22/33
SS01-04Interim efficacy analysis
of Phambili study
Background
� Step sister study conducted in South Africa
� In September 2007, because of results of the Step study, vaccinations
were suspended but follow up
Objective
� To compare rates of HIV acquisition among vaccine vs. placebo
recipients
Methods� Pre-unblinding and post-unblinding data
� 801 participants enrolled, 7% received all 3 study injections; 66%
received two; and 27% received one
8/7/2019 Clinical Trials (Mauro Schechter)
http://slidepdf.com/reader/full/clinical-trials-mauro-schechter 23/33
OA04-01Safety and immunogenicity of
LIPO-5, a HIV-1 lipopeptide vaccine
Background
� The vaccine includes 5 long peptides, containing multiple
CD8+ and CD4+ T-cell epitopes
� Phase 1 studies have shown that vaccine dosage at
500 g/lipopeptide elicits cellular immune responses
Objective
� Investigate if HIV-LIPO5 immunogenicity varies with thedosage
Methods
� ELISpot and PBMC lymphoproliferation were assessed at
baseline, two weeks after each injection, and at week 48
8/7/2019 Clinical Trials (Mauro Schechter)
http://slidepdf.com/reader/full/clinical-trials-mauro-schechter 24/33
OA04-02
� Strong HIV-specific CD4 and CD8 T-lymphocyte
proliferation in HIV-1 DNA prime/ modified vaccinia virus
Ankara (MVA) heterologous boost vaccinees
OA04-03
� Characterization of cell-mediated immune responsesgenerated by recombinant modified vaccinia Ankara
(rMVA)-HIV-1 in a phase I vaccine trial
8/7/2019 Clinical Trials (Mauro Schechter)
http://slidepdf.com/reader/full/clinical-trials-mauro-schechter 25/33
OA04-05Safety and viral load changes in HIV-1 infected
subjects treated with autologous dendritic immunetherapy following ART discontinuation
Background
� In a phase 1 trial, immunotherapy consisting of a
monocyte-derived dendritic cells and RNA encoding
autologous HIV antigens derived from the patient¶s own
pre-ART plasma induced immunogenicity in most patients
Objective
�Assess the safety and proportion of patients demonstrating
viral load < 1000, <5000 and <10,000 copies/mL during
the 12 week ART structured treatment interruption (STI)
8/7/2019 Clinical Trials (Mauro Schechter)
http://slidepdf.com/reader/full/clinical-trials-mauro-schechter 26/33
TAKE HOME MESSAGES
8/7/2019 Clinical Trials (Mauro Schechter)
http://slidepdf.com/reader/full/clinical-trials-mauro-schechter 27/33
Take home message # 1
How to interpretwhat scientists predict a trial will show
8/7/2019 Clinical Trials (Mauro Schechter)
http://slidepdf.com/reader/full/clinical-trials-mauro-schechter 28/33
³All predictions are difficult,
particularly when theyinvolve the future´
Dan Quayle
Former US Vice-President
8/7/2019 Clinical Trials (Mauro Schechter)
http://slidepdf.com/reader/full/clinical-trials-mauro-schechter 29/33
Take home message # 2
How to interpretwhat reputable scientists mean when
they criticize trials that will be
conducted by other reputable scientists
8/7/2019 Clinical Trials (Mauro Schechter)
http://slidepdf.com/reader/full/clinical-trials-mauro-schechter 30/33
³If we knew what we aredoing, we wouldn't call it
research.´
± Albert Einstein
8/7/2019 Clinical Trials (Mauro Schechter)
http://slidepdf.com/reader/full/clinical-trials-mauro-schechter 31/33
Take home message # 3
How to interpretwhat scientists say
they have learned from a trial
8/7/2019 Clinical Trials (Mauro Schechter)
http://slidepdf.com/reader/full/clinical-trials-mauro-schechter 32/33
³Half of what we havetaught you is wrong.
Unfortunately, we do notknow which half.´
± C. Sidney Burwell, M.D.
Address to the graduation class
Harvard Medical School