The (frequently long, circuitous,
and bumpy) trip from clinical
problems to clinical trials
Bill Burman
Denver Public Health
© 2014 Denver Public Health
One view of clinical trials
© 2014 Denver Public Health
Clinical trials: cautionary notes
• Time for a Phase 3 trial – a decade (or more!)
– Trial development – 1 to 5 years, trial conduct – 4 to 8
years, trial analysis – 1 to 2 years
– Will the question be relevant in 10 years?
• Cost of classic clinical trials (GCP, professional site
monitoring):
– $5-25,000 per patient/year
– For a trial of 1000 patients, $5 million to $25 million per
year of the trial
• Opportunity cost
– Limited funding for TB clinical trials – Is this a durable and
critical question?
© 2014 Denver Public Health
Another view of clinical trials…
© 2014 Denver Public Health
Problems of not doing clinical trials: When
to start ART
• When to start antiretroviral therapy (ART) –
classic case for a randomized trial
– Important clinical and programmatic question
– Randomization possible at the level of the
patient
• Challenges for “When to start” study
– Shifting equipoise
– Concerns about feasibility
© 2014 Denver Public Health
Shifting recommendations for “When to
start ART” – IAS USA panel
> 500
350-500
VL>30K
VL>5K
VL>10K
VL>5K
VL>5K
200-350
<200
CD4
© 2014 Denver Public Health
1996 1998 2000 2002 2004 2006 2008 2010
Shifting recommendations for “When to
start ART” – IAS USA panel
> 500
VL>30K
VL>5K
VL>10K
VL>5K
VL>5K
350-500 “It is questionable
whether a randomized
200-350 trial to study the issue of
When to Start will ever
<200 be feasible.”
2002 guidelines
CD4
© 2014 Denver Public Health
1996 1998 2000 2002 2004 2006 2008 2010
Shifting recommendations for “When to
start ART” – IAS USA panel
> 500
VL>30K
VL>5K
VL>10K
VL>5K
VL>5K
350-500 “It is questionable
whether a randomized
200-350 trial to study the issue of
When to Start will ever
<200 be feasible.”
2002 guidelines
CD4
© 2014 Denver Public Health
1996 1998 2000 2002 2004 2006 2008 2010
When to start ART: Potential of ART
• Prevent classic AIDS outcomes
• Prevent irreversible loss of immune
function (clonal deletion)
• Prevent other serious events:
– cardiovascular, renal, and hepatic events
– other cancers
– neurocognitive dysfunction
• Prevent HIV transmission
© 2014 Denver Public Health
When to start ART: Problems of ART
• Short-term side effects – diarrhea, rash, etc.
• Long-term metabolic effects
– Hyperlipidemia, bone loss
– Renal and hepatic toxicity
• Behavioral disinhibition – leading to increased risk
of transmission
• Acquired drug resistance, transmitted resistance
• Cost of antiretroviral therapy – drugs, monitoring,
increased clinical care
© 2014 Denver Public Health
SMART study – ART-naïve or off ART for >
6 months
• CD4 > 350
• Randomized
– Immediate ART
– Deferred ART: start when CD4 < 250
– ART: physician/patient choice
• 477 enrolled (of 5472 in overall trial)
– 249 ART-naïve
– 225 off ART for > 6 months
• Median follow-up – 18 months
© 2014 Denver Public Health
Rate per 100 person-years
Outcomes of SMART sub-study of “When
to Start”
8
7
6
5
P = 0.002
P = 0.02
P = 0.01
4
3
2
1
0
AIDS/death
Serious non-AIDS
< 250
© 2014 Denver Public Health
Composite
> 350
SMART Study Group. J Infect Dis 2008; 197: 1133-44
Lessons of the “When to start ART”
controversy
• > 15 years of controversy not resolved by many,
increasingly large and increasingly sophisticated
observational studies
• Clarity provided by two relatively small
randomized clinical trials (combined n = 1293,
with median follow-up for < 2 years)
• Recommendations for common, important clinical
decisions should be based on randomized trials
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Examples of the problems of not doing
clinical trials: TB
© 2014 Denver Public Health
Examples of the problems of not doing
clinical trials: TB
• Sub-optimal treatments
– Dosing of 1st (and 2nd) line TB drug in children
– MDR-TB regimens without clarity on critical questions
(e.g., number of drugs, length of aminoglycoside use,
selection of fluoroquinolone)
• Uncertainty about managing toxicity
– Drug-related liver injury
– Dosing of PZA, use of PZA in higher-risk patients
• Key details about 1st-line therapy
– Optimal duration
– Intermittency – when during treatment, degree
© 2014 Denver Public Health
Getting started
• Identify a compelling clinical problem – important in terms of
diagnosis, treatment effectiveness, toxicity, prevention,
population control
• Find relevant observational studies
– Current practices
– Key outcomes: definitions, rates, associated factors, estimation of the
effect size of an intervention
• Consider doing research on what to do research on
– Survey clinicians: key questions, areas of equipoise
– Survey patients: outcomes of TB treatment that are important to
patients
– Formal decision analysis – cost-effectiveness modeling of various
forms of treatment of latent TB
© 2014 Denver Public Health
Getting started
• Identify a compelling clinical problem – important in terms of
diagnosis, treatment effectiveness, toxicity, prevention,
population control
• Find relevant observational studies
– Current practices
– Key outcomes: definitions, rates, associated factors, estimation of the
effect size of an intervention
• Consider doing research on what to do research on
– Survey clinicians: key questions, areas of equipoise
– Survey patients: outcomes of TB treatment that are important to
patients
– Formal decision analysis – cost-effectiveness modeling of various
forms of treatment of latent TB
© 2014 Denver Public Health
Getting started
• Identify a compelling clinical problem – important in terms of
diagnosis, treatment effectiveness, toxicity, prevention,
population control
• Find relevant observational studies
– Current practices (sometimes substantially different from guidelines)
– Key outcomes: definitions, rates, associated factors, estimation of the
effect size of an intervention
• Consider doing research on what to do research on
– Survey clinicians: key questions, areas of equipoise
– Survey patients: outcomes of TB treatment that are important to
patients
– Formal decision analysis – cost-effectiveness modeling of various
forms of treatment of latent TB
© 2014 Denver Public Health
Getting started
• Identify a compelling clinical problem – important in terms of
diagnosis, treatment effectiveness, toxicity, prevention,
population control
• Find relevant observational studies
– Current practices (sometimes substantially different from guidelines)
– Key outcomes: definitions, rates, associated factors, estimation of the
effect size of an intervention
• Consider doing research on what to do research on
– Survey clinicians: key questions, areas of equipoise
– Survey patients: outcomes of TB treatment that are important to
patients
– Formal decision analysis – for example, cost-effectiveness modeling of
various forms of treatment of latent TB
© 2014 Denver Public Health
Trials of treatment-shortening with
fluoroquinolones
• Rationale
– Mouse model studies – moxifloxacin allowed
treatment shortening to 4 months, especially if
substituted for INH
– Improved treatment completion, leading to improved
TB control
– Fluoroquinolones are well-tolerated, known to be safe
• Three Phase 3 trials undertaken
© 2014 Denver Public Health
Activity of moxifloxacin in combination therapy
in a mouse model of TB
Log CFU in entire lung
10
9
8
7
Untreated
2RHZ+4RH
2RHZM+4RHM
2RMZ+4RM
6
5
4
3
2
2.5 logs
1
0
0
1
2
3
4
Duration of treatment (mos.)
Am J Respir Crit Care Med 2004; 164:421-6
5
6
Concerns about fluoroquinolones for
treatment-shortening
• Toxicity/tolerability
– Uncertainty about safety in pregnancy, children, and
the elderly
– Concerns about possible cardiotoxicity from moxi
– Selection for resistance in M. tuberculosis might limit
2nd-line regimen potency
– Broad activity against common bacterial pathogens –
selection for resistant strains, C. difficile
• Lack of consistent activity in Phase 2 trials
• Opportunity cost
© 2014 Denver Public Health
Effect of moxifloxacin on 2-month sputum
culture conversion
100
90
80
70
60
50
40
30
20
10
0
82
71
80
71
64
Study 27
South Africa
Moxi
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63
Brazil
Comparator
60
55
Study 28
EMB
Effect of moxifloxacin on 2-month sputum
culture conversion
100
90
80
70
60
50
40
30
20
10
0
N = 102
N = 336
71
82
71
64
Study 27
South Africa
Moxi
© 2014 Denver Public Health
N = 150
80
63
Brazil
Comparator
N = 443
60
55
Study 28
EMB
Treatment-shortening using moxifloxacin
for drug-susceptible active disease
Relapses
• IRZE – 12 (2%)
• IRZM – 46 (9%)
• MRZE – 64 (12%)
2-month conversion
• IRZE – 83%
• IRZM – 85%
• MRZE – 87%
Gillespie S, et al. N Engl J Med 2014; 371: 1677-87
© 2014 Denver Public Health
TB clinical trials: drug-susceptible TB
• Lessons from the past decade
– Regimens for drug-susceptible disease must be
applicable to women of child-bearing age and children
– Don’t start Phase 3 trials of treatment-shortening
without compelling results from Phase 2
– Is treatment-shortening to 4 months the most
important question in treatment of drug-susceptible
TB?
– We are far to quick to conclude that a new regimen is
“safe and well-tolerated”
© 2014 Denver Public Health
Suppression of ventricular ectopy after
acute MI
• Sudden death is common after a heart attack
• Ventricular ectopy is a risk factor for sudden death
• Drugs are available that markedly suppress
ventricular ectopy
• In a pilot randomized trial, these drugs were welltolerated
• Clinicians started to prescribe these drugs to
suppress ventricular ectopy
© 2014 Denver Public Health
% of patients with > 70%
suppression
Efficacy in suppressing ventricular
ectopy
90
80
70
60
50
40
30
20
10
0
flecainide
encainide
moricizine
placebo
Am J Cardiol 1988;61:501-9
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Tolerability in Phase 2
Encainide
(n = 99)
Flecainide
(n = 103)
Moricizine
(n = 98)
Placebo
(m = 100)
Death
0
0
0
0
CHF
1
0
0
0
MI
0
0
1
2
Other SAE
0
1
0
0
Drug
stopped
2
3
6
7
Am J Cardiol 1988;61:501-9
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Mortality
Effect of flecainide, encainide on
mortality - data from Phase 3 (n = 1500)
9
8
7
6
5
4
3
2
1
0
total mortality
cardiac mortality
active drug
placebo
N Engl J Med 1989;321:406-12
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Lessons of the CAST study
• Fixing a surrogate marker may not fix the disease
and may even exacerbate it
• Other examples:
– post-menopausal hormone replacement therapy and
CVD risk
– effect of antiretroviral therapy on CVD risk
– effect of EPO on anemia in ESRD
• Sample sizes in most clinical trials are inadequate
to detect unusual but serious adverse effects
© 2014 Denver Public Health
TB clinical trials: drug-susceptible TB
• Lessons from the past decade
– Regimens for drug-susceptible disease must be
applicable to women of child-bearing age and children
– Don’t start Phase 3 trials of treatment-shortening
without compelling results from Phase 2
– We are far to quick to conclude that a new regimen is
“safe and well-tolerated”
– Is treatment-shortening to 4 months the most
important question in treatment of drug-susceptible
TB?
© 2014 Denver Public Health
Prospective study of tolerability of
treatment for pulmonary TB
• Multicenter prospective study – 4 regions of China,
sampling scheme to assure representative sample of
patients with pulmonary TB
• Baseline survey and labs
• Treatment: IRZE for initial treatment, Strep added for
re-treatment
• Symptom diary during treatment
• Repeat labs at 2 months
• Adverse events and TB treatment outcomes
evaluated using standardized criteria
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Demographic and clinical characteristics of
the cohort
Parameter
Number (% of 4304)
Median age (IQR)
42 (29 – 55)
Male/female
3082 / 1227
TB treatment history
© 2014 Denver Public Health
Primary
3556 (83%
Re-treatment
748 (17%)
Hep B S Ag positive
469 (11%)
History of drug reaction
118 (3%)
Hepatobiliary disease
23 (0.5%)
Gastroenteropathy
40 (1%)
Diabetes
51 (1%)
Other medical illnesses
103 (2%)
Lv Z, et al. PLoS One 2013
Adverse drug reactions
• Frequency
– 766 (17%) had an adverse reaction, 1.4% had a serious
adverse reaction, 1% hospitalized
– Liver dysfunction – 6.3%, 0.6% had serious hepatotoxicity
• Effect on TB treatment regimen
– 43% of those with adverse reaction had regimen changed,
5% stopped all TB treatment
• Effect on TB treatment outcomes
– 2.8% with adverse reaction had unsuccessful TB treatment
(vs. 1% of those without an adverse reaction)
– 19% of all unsuccessful outcomes attributed to adverse
reactions
© 2014 Denver Public Health
Adverse drug reactions
• Frequency
– 766 (17%) had an adverse reaction, 1.4% had a serious
adverse reaction, 1% hospitalized
– Liver dysfunction – 6.3%, 0.6% had serious hepatotoxicity
• Effect on TB treatment regimen
– 43% of those with adverse reaction had regimen changed,
5% stopped all TB treatment
• Effect on TB treatment outcomes
– 2.8% with adverse reaction had unsuccessful TB treatment
(vs. 1% of those without an adverse reaction)
– 19% of all unsuccessful outcomes attributed to adverse
reactions
© 2014 Denver Public Health
Adverse drug reactions
• Frequency
– 766 (17%) had an adverse reaction, 1.4% had a serious
adverse reaction, 1% hospitalized
– Liver dysfunction – 6.3%, 0.6% had serious hepatotoxicity
• Effect on TB treatment regimen
– 43% of those with adverse reaction had regimen changed,
5% stopped all TB treatment
• Effect on TB treatment outcomes
– 2.8% with adverse reaction had unsuccessful TB treatment
(vs. 1% of those without an adverse reaction)
– 19% of all unsuccessful outcomes attributed to adverse
reactions
© 2014 Denver Public Health
Comparison of hepatotoxicity risk among
antimicrobial agents
Drug
Hepatotoxicity
incidence per 100,000
courses
Amox-clav *
1-17
Comments
Generally benign
Telithromycin *
17
Withdrawn from the market
Levofloxacin *
0.02
Trovofloxacin *
6
Withdrawn from the market
Rifampin
70
Annals Intern Med 2008; 149: 694
Isoniazid
380
Annals Intern Med 2008; 149: 694
Pyrazinamide
430
Ann Intern Med 2002; 137: 640-7
* Andrade R, Tulkens PM. J Antimicrob Chemother 2011; 66: 141-6
In population-based studies, TB drugs are among the most common causes
of serious drug-related hepatotoxicity (Aliment Pharmacol Ther 2010;31:1200,
Gastroenterol 2008;135:1924)
© 2014 Denver Public Health
Changes in age-distribution among cases
of active TB (Hong Kong)
As transmission decreases, active TB becomes increasingly a
disease of the elderly
Wu P, et al. PLoS One, 2010
© 2014 Denver Public Health
Age-specific rates of active TB, by WHO
region
http://www.who.int/tb/publications/global_report/en/
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Toxicity considerations in treatment of
drug-susceptible disease
• INH and PZA are much more hepatotoxic than antibiotics
that have been removed from the market
• The new norm of TB:
– Elderly, increased prevalence of comorbid disease
– Higher risk of adverse effects, including hepatitis and CVD
• Encourage enrollment of elderly and “complicated
patients” into TB clinical trials
• Is it time for trials comparing interventions for toxicity
avoidance?
© 2014 Denver Public Health
Endpoints – How to define “better” (or
“not inferior”)
• Clinical endpoints (TB, relapse, death)
– Infrequent events in TB patients
– Postulated differences in clinical event rates (treatment
effect size) may be small
– Infrequent events analyzed as dichotomous endpoints
+ small effect size = large sample sizes
• Surrogate markers (EBA, effect on transaminases,
cholesterol, etc.)
– Continuous variables with large dynamic range =
markedly smaller sample size
© 2014 Denver Public Health
Endpoints – the lessons of CAST and
SMART
• Surrogate markers – quite reasonable for
initial studies, to generate hypotheses
• Effects of interventions may be much more
complex than their effect on one or more
surrogate markers
• Surrogate markers should not be relied on as
the basis for major clinical decisions/policies
© 2014 Denver Public Health
Dealing with complex clinical situations
• Heterogeneity of “MDR-TB”
– Primary vs. acquired
– Degree of resistance to 2nd-line drugs
– Different definitions of “resistance”
– Limitations posed by intolerance to 2nd-line drugs
– Severity of pulmonary disease
• Common conclusion – Impossible to do clinical
trials for MDR-TB
© 2014 Denver Public Health
Example of “optimized background
regimen” design for MDR-HIV
• Study population
– Prior therapy with NRTI, NNRTI, PI
– Virological failure of current therapy (VL > 5000)
• Randomization
– Optimized Background Regimen (OBR) chosen by
enrolling clinician – could include other
investigational drugs
– OBR + T-20 (enfuvirtide)
© 2014 Denver Public Health
T-20 trial: baseline characteristics
Characteristic
T-20
Control
Previous ART
> 5 PIs
Lopinavr/R
Tenofovir
49%
39%
3%
39%
28%
0
Viral load
< 40,000
> 40,000
20%
80%
20%
80%
N Engl J Med 2003;348:2175-85
© 2014 Denver Public Health
T-20 trial: baseline characteristics
Characteristic
T-20
Control
Genotypic susc. Score
0
1-2
3-4
>5
16%
52%
28%
4%
13%
56%
27%
2%
Use of other investigational agents
Lopinavir/R
Tenofovir
62%
8%
62%
7%
N Engl J Med 2003;348:2175-85
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T-20 trial – efficacy results
N = 501
N Engl J Med 2003;348:2175-85, N Engl J Med 2003;358:
© 2014 Denver Public Health
T-20 trial – efficacy results from paired trials
N = 501
N Engl J Med 2003;348:2175-85, N Engl J Med 2003;358:
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Clinical trials for complex problems
• Don’t try to over-simplify life – manage
complexity, don’t try to eliminate it
• We under-estimate the power of
randomization to deal with clinical
heterogeneity
© 2014 Denver Public Health
Alternate trial designs
• Behavioral or system-level interventions (e.g., DOT
vs. SAT, availability of rapid susceptibility testing,
community-based testing to decrease TB
transmission)
– Cluster-randomized
– Stepped-wedge trial
© 2014 Denver Public Health
Alternate trial designs
• Behavioral or system-level interventions (e.g., DOT
vs. SAT, availability of rapid susceptibility testing,
community-based testing to decrease TB
transmission)
– Cluster-randomized
– Stepped-wedge trial
© 2014 Denver Public Health
Andrew Nunn’s rules for clinical trials
1. Ask important questions
2. Use simple designs
3. Enroll enough patients to answer the
question
My corollaries
• Don’t rush to trial design; do research
on what to do research on
• Seek out – don’t avoid – a wide range
of feedback on the design are worthy
© 2014 Denver Public Health
Andrew Nunn’s rules for clinical trials
1. Ask important questions
2. Use simple designs
3. Enroll enough patients to answer the
question
My corollaries
• Don’t rush to trial design; do research
on what to do research on
• Seek out – don’t avoid – a wide range
of feedback on the design are worthy
© 2014 Denver Public Health
Closing thoughts
• Clinical trials
– Not for the faint of heart
– Not for the impatient
– Not for the loner collaborative exercise,
political process
– But the team can
accomplish something
big
© 2014 Denver Public Health
Closing thoughts
• Clinical trials
– Not for the faint of heart
– Not for the impatient
– Not for the loner collaborative exercise,
political process
– But the team can
accomplish something
big
© 2014 Denver Public Health