Randomized prospective designs

 
The randomized controlled trial.
The basic flaw in all other designs is the problem of bias and is the root of considerable
controversy in the interpretation of the study results. The randomized controlled trial is the
ideal study design in that, when properly conducted, all potential sources of bias are eliminated
for the comparison of interest. In many situations a randomized trial is impossible to conduct
for practical and/or ethical reasons, in which case evidence from some of the other research
designs must suffice. But where randomization is possible, then it is the simplest way in which
to reach a definitive conclusion on the efficacy of a new product, procedure or treatment.
Example Infertile couples where the male partner was diagnosed as having poor
semen quality of unknown aetiology and the female partner was ‘normal’ were randomized to
receive clomiphene citrate or placebo daily for 6 months. The endpoint was pregnancy.
Example Women attending family planning clinics requesting an intrauterine device
were randomized to receive the standard or experimental device, and followed for up to 7 years
or until removal of the device.
The strength of the randomized controlled trial resides in three main features—the use
of a concurrent control group that is followed and managed in exactly the same way as the
experimental group, the lack of knowledge of the patient, the assessor or the physician of which
group the subject belongs to, and the use of randomization to ensure balance. Careful adherence
to these principles allows the strong inferences to be drawn from the study:
Everything is identical between the two groups of subjects (experimental and control)
apart form the different treatments under study. Hence any observed differences must be due to
the treatment effect.
The maximum degree of blindness given the experimental material and design should be
used wherever possible in an controlled clinical trial. At the time of enrollment the physician
should not know to which treatment the patient will be assigned; this will avoid any deliberate
or unintentional bias in selecting patients with better prognosis to one or other treatment group.
The patient should not know which treatment is received; this ensures that he is not reacting to
the presumed benefit of the
new therapy, or to any potential adverse effects. The study personnel who record or evaluate the
patient’s response or take decisions about the termination of participation in the trial should be
unaware of the treatment group assigned; this ensures that all groups are equally and fairly
evaluated.
The use of concurrent controls are essential to permit strict adherence to the
randomization and blindness that are such central features of the design. Often a placebo control
group is used where this is possible, for example if inert tablets can be packaged in an identical
manner to the active compound. Placebo controls are seldom possible in the comparison between
highly effective treatments (such as in contraceptive studies), but in situations where there is
doubt as to the efficacy of treatment the placebo controls can and should be used. For
contraceptive studies, the randomization may be between the new and the standard method.

12 Therapeutic studies
 
12.1 The Randomized Controlled Trial (RCT)

 
 The RCT is widely held as the ultimate study design; the "gold standard" against
which all other designs are compared. The sequence of an RCT (parallel) design is shown below.
The subjects are usually chosen from a large number of potential subjects. Sampling
includes prescreening using a set of inclusion and exclusion criteria. After this, an informed
consent is obtained from each participant. Randomization is then done to allocate subjects to
either the treatment group or the placebo group Randomization achieves two important things:
allocation to different treatment groups is done without bias because it is taken out of bands of
the investigator, and, importantly, randomization distributes known are unknown confounders
equally between the two treatment groups. Thus a good baseline comparability is ensured
between the two arms.
Once randomization is done, intervention is begun. Ideally, intervention should be done
in a blinded fashion. Neither the investigator nor the subject should know the nature of the
treatment that is being administered. After the intervention, the key outcomes that are being
studied need to be measured by a blinded investigator Analysis involves looking for
differences in the outcome rates in the two arms of the trial.

Thus, the core questions in a RCT are:

• Is the trial justified?
• Is the control group appropriate?
• Is the allocation landomized?
• Is the intervention blinded?
• Is the outcome ascertainment blinded?
• Is analysis by intention-to-treat principle?
Is the trial justified?
The first issue in any clinical trial is whether it is appropriate to do a trial at all. It is
widely held that to justify a clinical trial there needs to be a state of equipoise. Freedman defines
equipoise thus: "There is no consensus within the expert clinical community about the
comparative merits of the alternatives to be tested" [Freedman B
1987] In other words, if the investigator is sure that the new therapy is better than the earlier
one, then he/she is not justified in doing a trial. Equipoise, in this case, is disturbed by the fact
that evidence favors the new treatment when compared with the earlier one. In such a state it

 
 would not be fair or ethical to subject one group of the trial to an inferior therapy.
Equipoise is both a fascinating and difficult concept. It is the responsibility of every
clinician to prove (to an ethical committee or review group) that equipoise does exist before
starting a trial. At times, equipoise can be disturbed even when the trial is midway. New
evidence from other studies may settle the research question and disturb equipoise that
existed at the time of the launch of the trial. In such situations, the trial needs to be terminated
even before completion. Early termination of a trial
can be a very difficult and painful decision to the trial investigators and the trial
participants. Safety of the subjects and their interests are ultimately more important than the
research study.
Is the control group appropriate?
A recent controversy will serve to highlight this issue. In a recent paper titled "Unethical
trials of interventions to reduce perinatai transmission of the HIV in developing countries," Lime
and Wolfe managed to raise a lot of dust in the research circles! According to them, many trials
currently underway, which study the effect of the drug AZT to reduce perinatal transmission of
HIV are unethical. In 1994, a trial called ACTG 076 clearly demonstrated the efficacy of AZT
in reducing the incidence of HIV infection among babies born to HIV-positive mothers by two-
thirds. After that
study, the standard of care for HflV-positive pregnant women became the ACTG 076 regimen.
Despite this, several studies (including those supported by major institutions like CDC and NIH)
are being conducted in developing countries where several AZT regimes are being compared
against placebo arms. According to Lurie and Wolfe, this is unethical because several
mothers and babies are being denied AZT even though it is known that AZT is effective.
They also argue that most of these trials will never be allowed in developed countries on ethical
grounds. The arguments following their paper are equally fascinating and a must read for those
who are interested in the ethical issues of a clinical trial.
Can a placebo arm be justified when there is a therapy already available? Many
authors argue that it is unethical to do a placebo controlled study when some therapy is already
existent. No patient should be denied some form of therapy even if it is not very effective.
Mienert offers the following requirements for the test and control treatment:
• They must be distinguishable from one another
• They must be medically justifiable
• There must be an ethical base for use of either treatment
• Either treatments must be acceptable to study patients and to physicians
administering them
• There must be reasonable doubt regarding the efficacy of the test treatment
There should be reason to believe that the benefits will outweigh the risks of the
treatment
Is the allocation randomized?
Once the eligible subject has agreed to participate in the trial, it is important that
assignment to treatment or control group is done in a manner that is free of any selection bias.
To avoid bias, neither the patient nor the physician should be aware of
the group to which the patient will be allocated. This is done by randomizing blinded
fashion.
Randomization also ensures that the baseline characteristics of the test and the control
groups are more or less similar in order to provide a valid basis for comparison. If

 
 allocation is not randomized, there is always room for suspicion: it is possible that subjects with
favorable characteristics may be allocated to the treatment group while those with less favorable
characteristics may be allocated to the control group.
Is Blinding achieved?
The aim of blinding is to ensure that outcome ascertainment is done without any bias.
Blinding is logistically difficult but essential. Some authors use the word "masking" instead
of blinding. A single-blinded trial in which the patient is not informed of the treatment
assignment. A double-blinded trial is one in which neither the patient nor the physician
responsible for the treatment is informed of the treatment assignment:
RCTs usually report the effectiveness of blinding. Sometimes, known adverse effects of
drugs may unblind the physician (e.g. bradycardia due to beta blockers). Ideally, data
collection, measurement, reading and classification procedures on individual patients should be
made by persons who are completely blinded. For instance, if chest radiographs have to be
read, the films can be sent to another site where they are read by radiologists who have no
idea about the patients or their treatment groups.
As far as possible, outcomes chosen (end points) should be objective and clinically
relevant. Outcomes should be capable of being observed in a blinded
fashion. For instance, pain is a very subjective outcome and difficult to measure in a blinded
fashion. On the other hand, if the outcome is a biochemical parameter, then it is objective and
can be easily blinded.
Is analysis by intention-to-treat principle?
This is a very important issue in the analysis of RCT results. All patients allocated to
each arm of the treatment regimen are analyzed together as representing that treatment arm,
whether or not they received or completed the prescribed regimen. Failure to follow this defeats
the main purpose of randomization and can invalidate the results. For instance, if a patient
had been originally randomized to receive placebo, and if, for some reason, he actually ended
up getting the study treatment, for the purposes of analysis, this patient will still be counted as
belonging to the placebo group.
Ethical issues in a clinical trial
• Is there equipoise to justify the trial?
• Is informed consent obtained?
• Is confidentiality protected?
• Is the choice of control group justified?
• Early stopping rule specified?
It is now imperative that all clinical trials be cleared by an ethical committee or
Institutional Review Board (IRB). The issue of equipoise and choice of control group has
already been discussed. Informed consent is another important issue. The potential participant
should be made aware of the fact that he/she could end up getting only a placebo and the risks
of adverse events or even death should be explained before obtaining the consent.
Confidentiality also needs to be protected.
In some situations, the trial may need to be terminated early. In several trials,
independent data monitoring and safety committees periodically analyse the results of the trial.
If there is a significant difference between the treatment groups during the interim analysis, a
decision to terminate the trial may be made. This is to prevent the participants from being
exposed to an inferior form of therapy. Early termination may also be done if the frequency of
adverse events or deaths is unacceptably higher in any of the arms.

 
 Understanding the results of a clinical trial
Consider a clinical trial comparing a new antibiotic drug 'Bactex' for bacterial meningitis
against the conventional antibiotic therapy (control group). The outcome of the trial is the
mortality rate in each arm. These are dichotomous outcomes (alive or dead). At the end of the
trial we would have the death rate among those who got Bactex, .and death rate among the
control group. If the death rate among those who got Bactex is much lower than the rate among
the control group, that would be a result in favor of the new drug.
Let us now assign numbers for this hypothetical trial. If the death rate among those who
got Bactex was 20% and among the control group it was 40%, then these results could be
presented in many ways:
Absolute Risk Reduction: ARR is simply the difference between the death rates:
40% minus 20% = 20%. Bactex reduced the risk of mortality by 20%.
Relative Risk Reduction: If 40% of the control group died, what fraction of this would have
been prevented if the control group had received Bactex. This percentage is called Relative Risk
Reduction (RRR).
RRR = Outcome rate in control group - Outcome rate in the treatment group
Outcome rate in the control group
RRR = 40% - 20% = 50% 40%
A RRR of 50% means that Bactex reduced the risk of mortality by 50% relative
to that occurring among control group. The greater the relative risk reduction, the more
effective the new therapy.
Number Needed to Treat
The Number Needed to Treat (NNT) to prevent one adverse event is a novel way of
expressing results of trials. It attempts to overcome an inherent weakness in expressing results
as RRR. For example, if the risk was reduced from 10% to 5% by Bactex, the RRR would
still be 50%. In this situation, the overall death rate is quite low and this is not taken into
account by the RRR. The NNT is nothing by the inverse of the ARR [NNT=l/ARR].
In the earlier case, the ARR was 20%. I divided by ARR would be the NNT. In this
case it is 5. In other words, 5 patients would have to be treated to prevent one patient from
dying. Consider the alternative scenario where the event rate is very low:
10% rate among controls versus 5% rate among the Bactex arm. In this case, the NNT is 20.
So, 20 patients would now have to be treated to prevent one death. The lower the NNT, the
more effective the new therapy is. All the above measures of outcomes can be summarised as
a table (Table nr. 9):
Table nr. 9 Results of a clinical trial
Risk with Risk with new Absolute Risk Relative Risk Number
conventional therapy Y Reduction X-Y Reduction X- Needed to
therapy Y/X Treat 1/X-Y
(baseline risk)
X
40% 20% 40%- 20% = 20%/40% = l/20%=5
20% 50%
10% 5% 10%-5% = 5% 5%/10% = l/5%=20
50%

 
 Precision of rates
All the above rates are only point estimates. Along with these rates, one would have to report
the 95% confidence intervals to clearly express the significance of the results. 95% Cl can be
calculated for all these measures: ARR, RRR, and NNT.
Consider the scenario where we got a RRR of 50%. If the 95% Cl for this point
estimate were to be-10%- 80%, then we would infer that if the trial were to be repeated several
times, we could get an extreme result of minus 10% RRR (the new therapy performs worse
than the conventional therapy). If we got such a wide 95%Cl, we would have to conclude
that the new therapy is no better than the conventional therapy. The P value this case would
not be significant.
In the other case, we got a point estimate of 50%, and if the 95% Cl were 40%
to 60%, then would infer that even the worst performing trial would still give us a
40% RRR. This result could be reported as statistically significant [P value would be
< 0.05], and the new drug would be considered significantly better than the conventional drug.
It is easy to appreciate that smaller the trial, wider would be the confidence interval.
In very small trials, it is virtually impossible to get a statistically significant difference in the
outcomes. The trial would not have adequate 'power' to pick up a genuine difference even
if it truly exists.

The moral obligation to design a good trial

Experimental designs pose many dilemmas. On the one band, it may be unethical to
introduce into general use a therapy or drug which is totally untested or poorly tested. As
Sir Austin Bradford Hill put it "The ethical problem is, indeed, not solely one of human
experimentation; it can also be one of refraining from human experimentation.". On the other
hand, to paraphrase Hulley, a clinical trial should not be undertaken when, because of the
absence of randomization, blinding, or sufficient number of subjects, it is unlikely to provide
a conclusive answer. Indeed, it is important that a researcher embarking on a clinical trial
make every effort to design the trial well and pay attention to all the core issues in the trial.
It is quite common to see reports concluding that no inference could be made about the
efficacy of the new treatment because of inadequate sample size! Why put human lives at risk,
and spend a lot of resources when the research question is unlikely to be satisfactorily
answered?