Placebo control in clinical trials –
why always at least a category B trial?
Introduction
The categorical risk classification “B” for clinical trials with a placebo arm has
provoked numerous discussions within academic research. The main point of debate refers
to trial examples where it might be reasonably assumed that risk classification “B”
would not reflect the risk that the patient is exposed to, as the addition of a placebocontrol arm does not necessarily increase the risk for the study patient. For these
studies the administrative burden imposed with the category B might exceed the existing
capacities within the academic setting. In addition, the production of placebos
according to Good Manufacturing Practices (GMP) overruns the Investigator Initiated
Trial (IIT) budget easily. The academic research community fears impacts on the validity
of the IITs as investigators might abstain from performing placebo-controlled trials due
to the strict categorisation B.
The protection of patients and volunteers in clinical research has highest priority for
all stakeholders. According to the Human Research Act (HRA), the categorisation of
clinical trials and research projects depends on the risk patients and volunteers will
be exposed to. The Clinical trials Ordinance (ClinO) specifies that study projects
belonging to category A fall directly into category B when a placebo control group is
added.
Is it justified to penalise the methodological valuable input of a placebo control with
a higher risk categorisation and hence, increased administrative workload?
As the central cooperation platform for patient-oriented clinical research in
Switzerland, the Swiss Clinical Trial Organisation (SCTO) supports transparency in
clinical research and follows the current developments closely. Over the past few
months, the SCTO and the CTU network have therefore discussed possible simplifications
with Swissmedic. This valuable exchange has shown that although a change of the
categorisation
is
not
possible
under
the
current
law,
the
already
existing
simplifications are probably not known and exploited well enough.
This paper is intended to summarise the rationale for category B for randomised (doubleblind) placebo-controlled trials as per current law and to elaborate the simplifications in
the approval procedure already in place. If they are followed, the additional burden as
compared to category A remains moderate.
Thoughts about placebo and its
impact on clinical trials and
study participants
Beecher’s
publication
“The
powerful
1
placebo”
was the starting point for
research with placebos. Since then it is
widely recognised that the placebo itself
does not have any impact to the organism,
but the act of administering or using the
placebo
leads
to
a
reaction.
This
phenomenon led to the introduction of
randomised
clinical
trials,
aiming
to
prevent a certain placebo reaction that the
verum might have. With the placebo control,
the effect of the act of administration may
be subtracted from the real effect of the
verum medication itself. It is an important
instrument
to
reliably
prove
the
effectiveness and safety of new substances
and treatments. It is surely in itself not
an instrument that puts patients at risk.
The Federal Act on Medicinal Products and
2
Medical Devices defines medicinal products
as products (…) used or claimed with a
medical impact on the organism (…). Placebo
is
not
explicitly
mentioned
nor
Investigational Medicinal Products (IMP) in
1
Beecher HK. The powerful placebo. JAMA. 1955;
159:1602-6
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2
Therapeutic Products Act TPA, Art. 4 (1) lit a
Info Sheet Placebo Trials, October 2015
general. Furthermore the Swiss legislation
does not specify provisions concerning the
manufacturing of IMPs. Swiss authorities
therefore refer to European guidance for
3
this purpose.
The EU Directive 2001/20/EC says that an
IMP may be a test product, the reference or
placebo.
However,
this
does
not
automatically support the idea that the use
of a placebo – be it an IMP or not – alters
the risk categorisation derived from the
verum.
Why is a change in risk category justified
all the same?
Manufacturing of study
medication for a placebocontrolled randomised trial –
GMP requirements
Non-compliance with GMP, like inadequate
random-isation, may put patients at risk
(e.g. if placebo and test product are
mixed-up in sequence). Additionally as a
consequence, wrong conclusions may be drawn
regarding the result of a trial (under- or
overestimation of effect). Provided that
the trial outcome leads by mistake to an
adaptation
of
a
treatment,
even
more
patients may be at risk in the end. So it
is not the placebo itself being an issue,
but an inaccurate manufacturing step.
Manufacturing,
which
includes
blinding,
randomisation and labelling of IMPs – verum
and placebo –, must follow the guidelines
2
for GMP (see also ). This is just as
inescapable as study staff must strictly
follow the guidelines for GCP.
Therefore, IMPs may only be manufactured in
premises
with
corresponding
manufacturing
licence issued by Swissmedic. If this is
respected, documentation requirements for the
IMP in category B are minimal.
ClinO Art.19 (4) allows
deviation from the standard
procedure in the presence of an
adequate rationale
clinical studies with marketed products and a
placebo arm to allow a downgrading to category
B. The rationale: low risk of the “IMP
placebo”. As described below, there is neither
a rationale nor a legal basis for a further
downgrading to category A.
General requirements for the use
of placebos in controlled trials
The explanatory power and the validity of
clinical trial results depend on reliable
manufacture and quality of all used IMPs.
International and national law does not
allow the use of IMPs without MA – be it
placebo or not – without review of its
quality by a competent authority.
IMPs without MA are manufactured or modified
with production steps not (yet) authorised,
particularly if blinded. These facts result in
a mandatory review by Swissmedic.
Safety reporting simplifications
In a standard category B trial, the full
safety reporting programme usually applies.
In case of a category B trial as it is
described here (and which would fall into
cate-gory A if it were not placebocontrolled), the following simplifications
are
offered:
With
regard
to
the
documentation of Adverse Events (AEs), at
least a summary of suspected (serious)
adverse drug reactions should be provided
at the end of the trial to comply with
legal
pharmacovigilance
reporting
requirements after unblinding. This means
that at least Serious Adverse Events (SAEs)
with a suspected relationship with the IMP
and as described in the trial protocol have
to be documented during the trial. There is
no obligation to document non-serious AEs.
As a general rule: the protocol must always
describe the defined safety measures and
proposed
safety
reporting
and
give
an
appropriate rationale when deviating from
existing rules.
The following references can be
used for further clarifications
The
use
of
an
IMP
without
Marketing
Authorization (MA) assigns the concerned
clinical trial to category C. Theoretically,
Placebo corresponds to such an IMP without MA.
Besides, a blinded IMP would not be given a MA
since it is solely used in the context of a
trial.
•
On Swissmedic website: Q&A related
clinical trials with medicinal products
•
Clinical
Guideline
•
Therapeutic Product Act (TPA) (HMG/LPTh)
(SR 812.21)
Swissmedic and the Federal Office of Public
Health (FOPH) used ClinO Art. 19 (4) for
•
Human Research
810.30)
•
Ordinance on Clinical Trials in Human
Research (ClinO) (KlinV/OClin) (SR 810.305)
3
http://ec.europa.eu/health/files/eudralex/vol4/2009_06_annex13.pdf
2 of 3
Trial
Act
Application
(HRA)
to
dossier
(HFG/LRH)
(SR
Info Sheet Placebo Trials, October 2015
•
Medicinal Products Authorisation Ordinance
(MPAO) (AMBV/OAMéd) (SR 812.212.1)
•
ICH Good Clinical Practice Guideline (ICH
E6; 1996) (GCP Guideline)
•
Pharmacopoeia Eur. 8.0 et Helv. 11
•
EU Directive 2001/20/EC
The SCTO would like to thank Swissmedic for
the good cooperation and kind support in
compiling this information sheet.
Contacts
Swiss Clinical Trial Organisation |
www.scto.ch
|
[email protected]
| 061 260 10 40
Petersplatz 13| 4051 Basel
On 14.10.2015 we decided to not release and publish this document as it does not provide
really new information.
[PW]
3 of 3
Info Sheet Placebo Trials, October 2015