WWW.ICAD-CISD.COM
New Prevention
Technologies
Workshop
Module 3:
Overview of
Prevention Research
UNDERSTANDING
THE RESEARCH
PROCESS
Clinical Trials Process
Lasts 12 – 18 months
Studies Safety
Phase I
Smallest group
of volunteers
For
Microbicides
Lasts 1 – 6 months
Studies Safety
Phase II
Lasts up to 2 years
Studies Safety &
Immunogenicity
Larger group
of volunteers
Phase IIB
“Test of Concept”
Lasts up to 2 years
Studies Safety &
Acceptability
Bigger than Phase II but smaller than Phase III
Used to determine what products to move to Phase III
Phase III
Lasts 3 – 4 years
Studies Safety &
Efficacy
Largest group
of volunteers
Licensure,
Manufacturing &
Distribution
Lasts 2 – 4 years
Studies Safety &
Efficacy
Sometimes simultaneous studies (HIV+ and penile)
For
Vaccines
Preclinical
The product pipeline
1 in
large-scale
efficacy
trials
8 in early
human safety
trials
Preclinical testing
More than 50
candidates
Early-stage
concepts
Source: Alliance for Microbicide
Development
None of this research would
be possible without the
willingness and dedication
of the study volunteers!
Experience of a trial participant
Family Planning
Informed
consent for
screening
Informed
consent
to enrol
Condoms +
experimental gel
Condoms +
placebo
Screening Visit 1:
Education about the
trial, HIV and pregnancy
test, sexually
transmitted infection
tests and treatment,
baseline data collected
Screening Visit 2:
Results of tests,
counselling,
education about
trial reinforced
Randomisation:
Participant
assigned by
chance to a
group
UNDERSTANDING
TRIAL RESULTS
What is a Successful Trial?
A Successful Trial
A successful trial is not necessarily one that yields a positive
result but one where the:

Research plan conducted as stated & sound methodology

Trial provides further information

Health of participants protected

Trial continuously monitored at defined intervals

Participants & community engaged with the research process in
an ethical respectful, and efficient manner

Study results communicated to participants, community &
stakeholders

Plan for access to study product developed in case of + result
Scenario #1: Benefit (It Works!)


Trial shows compelling evidence of benefit
Examples:
 Male Circumcision (3 trials)
Scenario #2: Flat Result



The trial shows no benefit
The product caused no harm
Examples:
 Carraguard©, MIRA diaphragm
Scenario #3: Evidence of Harm




Trial shows product has no protection
Product causes harm
Usually, these trials will be closed early…
Examples:
 N-9, Cellulose Sulfate
Why might a trial
end early?
4 Reasons a Trial Ends Early
Evidence of Harm: There is evidence that the test
product may be causing harm.
Overwhelming Effect: The product being tested
is definitely effective and there is proof of efficacy.
Futility: In other words, the trial can no longer
answer the assigned question.
Concerns: Concerns may come from regulatory
bodies, community, or the trial sponsor.
Evidence of Harm: DSMB Stops
Study
DSMB stopped the CONRAD and FHI Cellulose Sulfate
studies in 2007
 CONRAD – Benin, India, South Africa, Uganda
 1,333 enrolled
 35 women seroconverted (23 in CS arm, 11 in placebo)
 DSMB met, saw possible evidence of harm, stopped
trial, alerted FHI
 FHI – Nigeria
 1,644 enrolled
 21 women seroconverted (approx. same in each arm)
 DSMB met, saw no evidence of harm, stopped trial to
err on the side of caution
Overwhelming effect:
Male circumcision



3 studies conducted: Orange Farm, Rakai, Kisumu
In 2006, DSMBs closed the studies early due to
overwhelming effect (from 51 to 60%)
WHO published recommendation
based on study results
Closed for Futility:
DSMB Discontinues One Arm
Data monitors can also stop part of a trial.
 MDP 301 Trial of PRO 2000: 2% and 0.5%
 DSMB closed 2% arm
 “as there is no more than a small
chance of the high dose
showing protection against
HIV infection compared to
placebo gel”
 Remaining .05% and
comparator gel arms continued
Concerns:
Study Ends Over Controversy
Political controversy can halt trials just as quickly as
scientific findings.

Miscommunication between
researchers and the
community led to political
controversy and halted PrEP
trials in Cambodia and
Cameroon in 2004.
All Clinical Trial Results Are Valuable




They can tell us which products are not worth pursuing
They can point to the kinds of modifications that could
be made to improve trial design
They may yield beneficial information about behavioral
and cultural practices that influence HIV transmission
and clinical trial outcomes; and
They provide valuable information about how
prevention trials can be better managed.
UNDERSTANDING
PREVENTION
TRIALS
HIV Prevention Trials Differ From
Treatment Trials
Treatment Trials:
 Enroll those needing
treatment – individual
urgency.
 May help prevent
disease progression.
 Only benefits those with
the disease.
HIV Prevention Trials:
 Enrolling healthy people –
no immediate benefit to
individual
 May help prevent disease
transmission.
 Benefits society; everyone
at risk of HIV.
Special Challenges of
HIV Prevention Trials

Complex clinical trial design: multi-site, multi-country, 2,00010,000 participants, transnational research collaborations

Healthy individuals -- yet at “high risk”: 3-5% annual incidence
minimum

Often involved marginalised or stigmatised populations (sex
workers, IDU, MSM); stigma associated with HIV, sexual
activity, drug use

All new intervention likely to reduce, not eliminate risk = require
large trials to detect partial efficacy

No clear surrogate endpoints (“correlates of protection”); only
new infections tell us whether a product works or not

Results affected by user behaviour, in many cases
Why are most of the phase III trials
taking place in Africa and Asia?


Microbicide trials require large numbers of women at
risk of vaginally transmitted HIV
 High incidence
 Relatively stable (non-transient population)
 Little or no injection drug use
Most populations of women in the US or Europe with
high HIV incidence also use IV drugs
Sample Size Calculations
Effectiveness
20%
30%
40%
50%
60%
70%
80%
90%
Annual HIV Sero-Incidence
1%
2%
3%
4%
110266
46315
24539
14736
9560
6529
4621
3353
54638
22965
12176
7320
4753
3249
2304
1673
36094
15181
8056
4847
3612
2158
1532
1115
26824
11289
5995
3609
2351
1612
1144
835
5%
21259
8955
4760
2868
1868
1282
913
666
Notes: Significance level = .05, power = 90%, test statistics and log rank test, two-tailed,
equal size groups. Assumes 15 percent loss to follow-up. Figures prepared by Charlotte
Ellertson and Kelly Blanchard using nQuery (version 1.0) survival analysis option.
Exercise: Outcomes of past studies
Signs of efficacy
Safe
Trend
toward
harm
No efficacy
What will NPTs mean for HIV
prevention?
The answer depends on us!
“Science teaches us
everything except
what to think and what to do.”
– Søren Kierkegaard