Projeto Praça OnzeUniversidade Federal do Rio de Janeiro

Clinical Trials at AIDS Vaccine ‘09

Scientific Journalists Training ProgramGlobal HIV Vaccine Enterprise

Paris, October 19, 2009

Mauro SchechterPrincipal Investigator, Projeto Praça Onze

Professor of Infectious DiseasesUniversidade Federal do Rio de Janeiro

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

Randomised Controlled Trials (RCTs)

• Experimental, (usually) longitudinal, prospective

• Randomised – ensures that treatment groups are similar at start of trial; any differences are due to chance only

• Controlled – control group allows to conclude that outcome is due to the test vaccine rather than some other factor

• Comparison is usually between a new regimen or intervention and an existing standard of care or placebo

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

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 control

group

Limitations of randomized clinical trials

Practical aspects of clinical trials

• Question being studied

• Trial population/Control group

• Trial design

• Analysis (pre-specified vs. post-hoc)

Practical aspects of clinical trials

• Question being studied

• Trial population/Control group

• Trial design

• Analysis (pre-specified vs. post-hoc)

Practical aspects of clinical trials

• Question being studied

• Trial population/Control group

• Trial design

• Analysis (pre-specified vs. post-hoc)

Trial populations

• Explicit and objective inclusion and exclusion criteria are required for any RCT

• Narrow and restrictive inclusion criteria can allow to focus on a specific group of people and reduce variability in the outcome

• However, included participants may not be representative of those who may receive the vaccine in the future

The need for a control group

• ‘Hawthorn effect’: observation that patients in clinical trials generally do better than similar patients on same treatment (closer monitoring, clear treatment plan, enthusiastic team, etc.)

• Therefore, a control group provides the opportunity to see ‘what would have happened without the new intervention’

The need for randomisation

• Patient allocation to new intervention or control groups 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 during the study period, any differences in outcome between the two groups can be attributed to the intervention

Practical aspects of clinical trials

• Question being studied

• Trial population/Control group

• Trial design

• Analysis (pre-specified vs. post-hoc)

Blinding

• Bias can occur if a patient or treatment team are aware of treatment allocation

• Patient: psychological effect on behaviour

• Clinical team: intensity of counselling

Types of RCTs

• Parallel group: each patient is randomised to receive only one of the two different strategies

• Crossover trial: each patient receives first one treatment strategy then the other, but the treatment order is randomised

• Cluster randomised: each ‘cluster’ of patients (hospitals, outpatient clinics) randomised to receive one of the two different treatment strategies

Parallel design trials

Randomisation

New intervention

Control group

Present time

Compare treatment

groups

Follow individuals

Starting point

Cross-over trials

Randomisation

New Intervention

Control group

Present time Future timeFollow individuals

Starting point

New Intervention

Control group

Wash out

Crossover trial

• Crossover trials are particularly useful for short term outcomes 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 the effect of the first treatment administered may carry over and alter subsequent responses

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

Clinical Trials at AIDS Vaccine ‘09

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

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

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

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 500µg/lipopeptide elicits cellular immune responses

Objective

• Investigate if HIV-LIPO5 immunogenicity varies with the dosage

Methods

• ELISpot and PBMC lymphoproliferation were assessed at baseline, two weeks after each injection, and at week 48

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 responses generated by recombinant modified vaccinia Ankara (rMVA)-HIV-1 in a phase I vaccine trial

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)

TAKE HOME MESSAGES

Take home message # 1

How to interpretwhat scientists predict a trial will show

“All predictions are difficult, particularly when they involve the future”

Dan Quayle

Former US Vice-President

Take home message # 2

How to interpretwhat reputable scientists mean when

they criticize trials that will be conducted by other reputable scientists

“If we knew what we are doing, we wouldn't call it

research.”

– Albert Einstein

Take home message # 3

How to interpretwhat scientists say

they have learned from a trial

“Half of what we have taught you is wrong.

Unfortunately, we do not know which half.”

– C. Sidney Burwell, M.D.

Address to the graduation class

Harvard Medical School

Merci !Thank You !Obrigado !