Transcript Document

The Randomized Controlled Trial
its Uses and Abuses
2006
Hasan Yazıcı
University of Istanbul
Plan
● Why am I giving this talk?
● Why am I giving this talk?
● RCT as a scientific tool
- Historical aspects
- RCT and efficacy
- reallocation to a failing medicine
- extension studies
- RCT and adverse effects
- the time element
- FDA and the time element
● What next?
Randomized Controlled Trials in BS
The Cerrahpaşa Experience
• Colchicine 1980, Haematologica
• Azathioprin 1990, N Engl J Med
• Alpha Interferon 1991, Br J Rheumatol
• Azapropazone 1995, Clin Exp Rheumatol
• Cyclosporine 1997, Int J Dermatol
• Thalidomide 1998, Ann Intern Med
• Colchicine 2001, Arthritis Rheum
• Etanercept 2005, J Rheumatol
• Steroids 2006, Rheumatology (Oxford)
“Forty percent of science news relates to
health and medicine and we are seeing a
gradual erosion of public trust.”
EA Zerhouni, Director NIH
PLoS Medicine 2006
Many people would simply say: “ We do this
because we need to get FDA approval for the
product.” Of course this is true but there is
deeper societal reason for trying to determine
medical products are useful. I am going to
review briefly how we got where we are today,
for pharmaceuticals in particular.
The efficacy requirement for pharmaceuticals
dates back to the thalidomide tragedy in the
late 1950s. Appalled by the concrete evidence
of a drug’s truly devastating, undetected side
effect, Congress decided that given the risks,
drugs should not have been allowed on the
market unless they had ben shown scientifically
to have some benefit.
J Woodcock (FDA) Clinical Trials 2005
Confidence?
•
Complications of the COX-2 Inhibitors Parecoxib and Valdecoxib after
Cardiac Surgery. Nussmeier NA et al. NEJM 2005 352 1081 -1091.
• “The authors had complete access to the data after unblinding.
All final analyses were conducted by an independent
statistician at the Texas Heart Institute in Houston. The data
reported here were those available to the authors as of
February 14, 2005.”
•
Cardiovascular Events Associated with Rofecoxib in a Colorectal Adenoma
Chemoprevention Trial. Bresalier RS et al. NEJM 2005 352 1092 -1102.
• “The data reported here are those available to the authors as of
February 14, 2005.”
The full texts of both articles appeared
in the electronic version of NEJM on
February 15, 2005.
Academic Medical Centers’ Standards for Clinical
Trial Agreements with Industry
Mello et al N Engl J Med, 2005
Randomized Controlled Trial
 Deductive
 Tries to dis-prove (falficify) a
hypothesis (Popperian)
The RCT and Efficacy
 As a scientific tool the starting
point of a RCT to study efficacy is
to falcify the hypothesis that the
new drug tested is superior to
conventional, other new or no
therapy.
 If this hypothesis cannot be
falcified only then the new
treatment can be taken as superior
to the other modalities.
K. Popper
TNF Inhibitors:
useful additional therapy to Methotrexate
in RA patients with severe disease
Only 3 (4?)/11 RCT’s with infliximab,
etanercept and adalimumab were
conducted among MTX naive
patients.
Yazıcı Y, Yazıcı H Arthritis Rheum 2006;54(suppl)
Yazıcı Y, Yazıcı H Arthritis Rheum 2006;54(suppl)
450
400
350
300
250
200
150
100
50
1
1.59
-0.54
ERA ETA
ERA MTX
TEMPO
Combi
0.52
2.8
0.4
3.7
1.3
3
5.7
IFX MTX
PREMIER
Combi
PREMIER
ADA
PREMIER
MTX
0
TEMPO ETA TEMPO MTX IFX Combi
Yazıcı Y, Yazıcı H Arthritis Rheum 2006;54(suppl)
Sins of Extension Studies
• Equipose
• Informed consent
• Power calculations
• Intent to treat
• Delaying useful treatment
• Changing of authors
• No new information
Equipose
In real hypothesis testing the likelihood
of proving or disproving your
hypothesis is approximately 50%.
Nihilistic view (JF Fries): RCT has
probably became obsolete
Randomized Controlled Trials in BS
The Cerrahpaşa Experience
• Colchicine 1980, Haematologica
• Azathioprin 1990, N Engl J Med
• Alpha Interferon 1991, Br J Rheumatol
• Azapropazone 1995, Clin Exp Rheumatol
• Cyclosporine 1997, Int J Dermatol
• Thalidomide 1998, Ann Intern Med
• Colchicine 2001, Arthritis Rheum
• Etanercept 2005, J Rheumatol
• Steroids 2006, Rheumatology (Oxford)
Sins of Extension Studies
• Equipose
• Informed consent
• Power calculations
• Intent to treat
• Delaying useful treatment
• Changing of authors
• No new information
Why can RCT be problemetic
when looking for both
Safety & Efficacy
• Short duration
• Limited number of patients enrolled
• Big differences (including other
medications used) between the
patients enrolled in a trial and seen
in real practice!
RA Patients in Real Life
fulfilling the entrance criteria to a
major RCT (ATTRACT, Lancet 1999)
Sokka et al:
42/229
(18.3%)
Gogus et al:
9/155
(6.0%)
Sokka T et al: J Rheumatol 2003
Göğüş F et al Clin Exp Rheumatol 2005
Merck Co., press release
September 4, 2004
“Merck has always believed that
prospective, randomized, controlled
clinical trials are the best way to
evaluate the safety of medicines.
APPROVe is precisely this type of
study—and it has provided us with
new data on the cardiovascular
profile of VIOXX.”
Peter S. Kim, Ph.D.
President of Merck Research Laboratories.
The RCT and Adverse Events
 As a scientific tool the starting point of a RCT to
study adverse events should be to falcify the
hypothesis that the new drug tested does have
more/serious adverse events when tested
against conventional, “other” new or no
therapy.
• When this hypothesis cannot be falcified only
then the new treatment can be said not to
have more adverse effects compared to other
modalities.
• Such undertaking would clearly be undesirable
for “deeper socieatal” concerns.
K. Popper
Adverse Events
The Time Element

....I think this is rather misleading. Of
the 26 lymphomas they refer to in the
main text, 14 occurred within 2 months
of TNF antagonist use. Thus, a more
realistic comparator would be a
deduced (from the annual rates) 2month incidence of lymphoma in the
general population....
H Yazici Arthritis Rheum 2003
Time to Adverse Effects
A survey of inclusion of the time element when reporting adverse effects in randomized
controlled trials of cyclooxygease-2 and tumor necrosis factor alpha inhibitors
Arthritis and Rheum
N Engl J Med
Ann Rheum Dis
JAMA
Rheumatology
Lancet
J Rheumatol
Ann Intern Med
Clin Exp Rheumatol
Am J Med
Arch Intern Med
Y Yazici and H Yazici Ann Rheum Dis, in print
Time to Adverse Effects
Drug
COX-2
TNF-α
Total
(n=26)
(n=44)
(n=70)
Number of patients
1541
216
mean; median; range
601; 67-8076
42; 20-1049
Number of publications
giving time to AE (%)
6 (23)
17 (39)
23(33)
Number of publications
giving time to serious AE
(%)
3 (12)
9 (20)
12 (17)
Annual incidence used as a
comparator (%)
0
8 (18)
8 (11)
Use of patient – years (%)
2 (8)
4 (9)
6 (9)
Y Yazici and H Yazici Ann Rheum Dis, in e. print
www.fda.gov/cder/guidance/3580fnl.pdf
Most applicants will construct adverse event tables by
compiling and presenting the numbers and/or
percentages of patients experiencing an adverse event
in a study (or the absolute number of adverse events
experienced in a group), without regard to the duration
of treatment received. This is often satisfactory for
relatively short-term studies. If studies of significantly
different durations are pooled, however, or if there is a
different discontinuation rate in the treatment arms
and the risk of the adverse reaction persists over time,
one must consider these durations to understand the
real occurrence rate that patients will experience. One
way to deal with the problem of different durations is to
use the total person-time exposure for each treatment
group and calculate the rate of the adverse event per
period of exposure (# of patients with adverse event
total person-time exposure), rather than the risk (# of
patients with adverse event total number of patients).
This is particularly useful for the more important
adverse reactions and reactions that occur at a
fairly constant rate over time, but the person-time
approach can also be used when the hazard rate
changes over time. In this case, however, the
observation period must be broken into component
periods (e.g., evaluating person-time rates for each
treatment for month 1, month 2, ....).
If concurrently controlled data are unavailable,
overall rates from well-monitored, single-arm
databases can be used to provide some indication
of rates that were observed in treated patients, but
there is little ability to establish causality except
insofar as reactions are predicted by the known
pharmacology of the drug.
For the most part, attributions of causality by the
investigators should be discounted, and adverse
events should be assessed without regard to
attribution.
Explorations for dose dependency. These are
important. The reviewer should ordinarily rely
on fixed dose studies, as titration studies tend
to show that those who tolerate higher doses
have lower adverse reaction rates, but in some
cases titration studies may show a clearly
increased rate of adverse reactions with dose.
It may also be useful to evaluate safety as a
function of weight-adjusted dose, body
surface-adjusted dose, or cumulative dose.
Dose increases may be associated with
adverse reactions or the severity of adverse
reactions.
For events that occur commonly, explorations
of time to onset for common, troublesome
events (e.g., somnolence, nausea) explorations
of adaptation to develop information on the
time course of, and tolerance for, such events
…..
7.1.6 Less Common Adverse Events
• In general, a fairly large database is needed to evaluate less
common adverse events. To identify relatively rare events of
significant concern, the reviewer has to examine the
occurrence of adverse events over the entire phase 2 to 3
database, including data for which there is no useful
concurrent control. The overall database is typically
heterogeneous, including uncontrolled exposure for varying
durations and at varying doses, and is unlikely to lend itself to
meaningful estimates of rates or assessment of causality
(except where there has been rechallenge). Thus, it may be
sufficient for the reviewer to group these data in gross
categories of incidence and by body system. For example, it
may be useful to categorize less common events in order of
decreasing frequency within the following incidence ranges:
• Adverse events occurring at rates less than or equal to 1/100
• Adverse events estimated to occur at rates between 1/100
and 1/1000
• Adverse events estimated to occur at rates less than 1/1000
•
•
•
•
•
•
•
The review should also provide overall conclusions
about the safety of the drug, including:
Overall assessment of the available safety
information, referring both to what it has shown and
its adequacy
The limitations of the available data
Additional information needed, including both further
analyses and additional studies.
Comparison, to the extent possible, of the safety of
the drug under review to the safety of other available
products, and the basis for that comparison (direct
comparative data vs. clinical opinion)
Whether a risk management program (beyond
labeling) is needed and why
Analysis of likely uses beyond labeling, (e.g., in more
severe patients, in other diseases, in children)
Whether there is a need for postmarketing safety
studies
For the most part, attributions of causality by the
investigators should be discounted, and adverse events
should be assessed without regard to attribution. Also,
in general, tables should give rates for all severities of a
given effect, although in some cases (notably cytotoxic
drugs), it is important to distinguish more and less
severe reactions, as the former may be therapy-limiting
or may affect the overall benefit-risk conclusion for the
drug. For events with high background rates (e.g.,
headache, fatigue, and other events that occur
frequently independent of drug therapy), however,
display of all reported events can result in a high event
rate that obscures drug-relatedness. This can be a
particular problem when time on drug is prolonged. For
example, it is common for studies of 4 to 6 weeks
duration to report headache at a high (20 to 25 percent)
rate. In that case, considering the severity or causality
assessment of such events may allow a better
assessment (e.g., if severe headaches are found only in
the drug-treated group). Events that are more severe
and for which subjects have multiple occurrences while
on drug therapy are more likely drug-related. In
determining incidence, however, both single occurrence
and multiple occurrence events should be counted as
one event.
Time to onset of Adverse Events
Strom BL ed. Pharmacoepidemiology,2000
Criteria
for the casual nature of an association
1.
Plausibility
2.
Consistency
3.
Time sequence
4.
Specificity
5.
Strength
a. Quantitative
b. Dose-response
c. Study design
Strom BL ed. Pharmacoepidemiology,2000
Neoplasia
Median: 19 weeks
Time to Neoplasia
14
Number with neoplasian
12
10
8
6
4
2
0
0-12
13-24
25-36
37-48
Weeks
49-60
61-72
72+
Based on T Bongartz et al JAMA 2006
Tumor necrosis factor-α antagonist use and
cancer in patients with rheumatoid arthritis
Arhritis Rheum 2006
The tumor necrosis factor (TNF ) antagonists, a type
of biologic DMARD with profound immunoregulatory
effects, have had a significant impact on the
treatment of RA. However, safety concerns regarding
these drugs arose after the Food and Drug
Administration's postmarketing spontaneous adverse
event reporting system (MedWatch) received reports
of lymphoma. Brown et al reviewed MedWatch
reports of 26 cases of lymphoproliferative disorders
that occurred following treatment with either of 2
TNF antagonists, etanercept or infliximab. The
extrapolated crude incidence of lymphoproliferative
disorders was 19.9 per 100,000 person-years for
etanercept and 6.6 per 100,000 person-years for
infliximab (16). Although these rates were smaller
than that in the general population, features of the
cases were of concern: in 54% of the patients who
developed lymphoma, it was detected within 8 weeks
after initiation of TNF antagonist treatment, and in 2
of these patients, it remitted after cessation of TNF
antagonist treatment.
Tumor necrosis factor-α antagonist use and
cancer in patients with rheumatoid arthritis
Arhritis Rheum 2006
DMARD exposure and potential confounders.
All patients included in the study had been prescribed a
biologic DMARD (etanercept, infliximab, adalimumab, or
anakinra) or MTX. Cohort followup started at the time of
the first prescription of a biologic DMARD or MTX during
the study period. Some patients contributed person-time
to multiple exposure categories. Patients who were
receiving both a biologic DMARD and MTX at the same
time were categorized as biologic DMARD users. We
assumed that the effect of the biologic DMARDs persists
from the initiation of its use until the end of followup,
testing the hypothesis that the effect of these agents on
cancer is both profound and long term (16). In a
secondary analysis, we assumed a 180-day induction
period and excluded that period from the followup time.
Drug Development
New Approaches
●Personalized medicines
●Bayesian approach
●Extrapolation of efficacy
J Woodcock Clinical Trials 2005
“It is timely and healthy to question the
real value of the controlled clinical trial as
the ultimate guide for evidence based
practice of medicine. Sometimes,
however, it is not the “controlled clinical
trial”, but its interpretation that needs to
be put on trial.”
H Yazici J Rheumatol 2004