Viewpoint
The Good Clinical Practice guideline: a bronze standard for
Lancet 2005; 366: 172–74
Family Health International,
Research Triangle Park, NC,
USA (D A Grimes MD,
D Hubacher PhD, K Nanda MD,
K F Schulz PhD); Chalmers
Research Group, Children’s
Hospital of Eastern Ontario
Research Institute, Ottawa,
ON, Canada (D Moher PhD);
and Centre for Statistics in
Medicine, Institute for Health
Sciences, Oxford, UK
(Prof D G Altman DSc)
Correspondence to:
Dr David A Grimes,
Family Health International,
PO Box 13950, Research Triangle
Park, NC 27709, USA
dgrimes@fhi.org
172
clinical research
David A Grimes, David Hubacher, Kavita Nanda, Kenneth F Schulz, David Moher, Douglas G Altman
Clinical researchers throughout the world are having to
abide by the Good Clinical Practice (GCP) guideline1
developed by the International Conference on
Harmonisation (ICH).2 In today’s evidence-based
climate, little evidence supports this guideline.
Moreover, the guideline diverts scarce research funds
towards compliance activities of unknown value.
Although the guideline’s goals of documenting
informed-consent, safety of participants, and integrity of
data are worthy, its development process was not ideal.
Obsolete at inception, GCP lags at least 10 years behind
the published work on research methods. Deemed a
“gold standard” by some,2 the guideline is at best a
bronze standard. In this Viewpoint, we highlight some
of these deficiencies, challenge the notion that GCP
should be widely applied to clinical research, and offer
practical solutions to the dilemma.
Background
Documentation of compliance with GCP is required for
all submissions approved by regulatory agencies in the
European Union, the USA, Japan, and Canada. A series
of numbered ICH “efficacy” guidelines have been
developed on various topics (E1 through E12A). This
voluminous material (now totalling 367 pages) can be
confusing (eg, when downloaded from different web
sites, some identical documents have different titles and
dates). The document on which we will mainly focus is
“Good Clinical Practice: Consolidated Guidance (ICH-
E6).” GCP “is an international ethical and scientific
quality standard for designing, conducting, recording,
and reporting trials that involve the participation of
human subjects.”1 Compliance is intended to assure that
the rights, safety, and wellbeing of participants are
protected, and that trial data are credible. We agree with
these goals.
Deficiencies of GCP
The term “Good Clinical Practice” is a misnomer
(table). This unofficial jargon refers to US Food and
Drug Administration regulations and guidelines
organised within the US Code of Federal Regulations.2
Unfortunately, other organisations, such as the UK
Medical Research Council, have adopted the GCP
misnomer. “Good Clinical Practice” here does not
relate to clinical practice, but, rather, to the conduct of
clinical research.
Four general approaches to guideline development
exist: informal consensus development, formal
consensus development, evidence-based guideline
development, and explicit guideline development.3
“Good Clinical Practice” derives from the weakest
approach, informal consensus.3 The International
Conference on Harmonisation states that “The ICH
process [informal consensus] has achieved success
because it is based on scientific consensus developed
between industry and regulatory experts.”9 Contrary to
this assertion, consensus-based guidelines are worse
than evidence-based guidelines.4 Although no methods
for development of research-practice guidelines
exist, GCP fails on most criteria when judged by
reproducible instruments for development of clinical-
practice guidelines.10,11
Despite expert consensus and external review by
industry and regulatory bodies, ICH-E6 is missing
important information.1 For example, the need for
adequate allocation concealment to avoid selection bias
in randomised controlled trials was published in 1995,8 a
year before ICH-E6 was published (1996). But despite its
supposed emphasis on scientific validity, the ICH-E6
guideline does not mention this key requirement for
such studies. This shortcoming might result from the
absence of a systematic up-to-date search for and
categorisation of the relevant published work.4
ICH-E6 has other deficiencies. The document has no
identified authors or contributors. Since it provides no
references, the scientific basis for its recommendations
is unknown. Not being included in PubMed, the
document is fairly inaccessible to the biomedical
research community. Guidelines, like grocery-store
produce, have a limited shelf life, after which they
should be discarded.12 ICH-E6 has not been updated
since 1996, and no timetable for revision is specified.
Unlike some clinical practice guidelines,13 this guideline
has not been shown to be of benefit.
The GCP development process omitted important
constituencies. Academic researchers did not participate
in GCP guideline development.6 ICH missed the
opportunity to build trust with the medical profession or
public-health advocacy organisations; indeed, “the
international regulatory-network ‘state’ suffers acutely
from a lack of public accountability.”6
GCP emphasises clinical monitoring and data audits
to confirm that clinical trial data are “verifiable from
source documents.”1 Key objectives are detection of
fraud and accurate transcription of data. We support
both goals, but whether the methods of GCP achieve
them is unclear. Although intensive monitoring of
clinical sites and auditing of research could help prevent
or detect fraud,14 “fraud in clinical trials is so rare and . . .
generally inconsequential, that the public may be far
more misguided by studies that are poorly designed,
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wrongly analysed and inappropriately reported than by
fraud.”15 Moreover, monitoring confirms consistency
between data collection forms and source documents; if
the source documents are wrong because of laboratory,
clinical, or clerical errors, then monitoring adds expense
without benefit. A common misinterpretation of
sponsors is that GCP requires audits of 100% of data; by
contrast, random audits might suffice.
Compliance with guidelines carries large, sometimes
insurmountable costs. Whether these added costs are
justified is unknown. For example, the US Food and
Drug Administration decided to mandate the use of
Good Manufacturing Practices (focused on process and
record-keeping for the pharmaceutical industry) for the
processing, testing, and transfusion of blood products.
The added administrative burden on US blood banks
has increased the cost of blood products by an estimated
US$226 million per year without any demonstrable
benefit.16 Similarly, research regimentation without
evidence of benefit at a reasonable cost is inappropriate.
Limited funds and human resources are available for
clinical research. If these funds are diverted from
activities that improve research quality (eg, keeping
losses of participants after randomisation to a
minimum) into activities that are unrelated to research
validity and reliability (eg, filing and updating of
curricula vitae, signature sheets, and tables of normal
laboratory values),1 the latter activities have a net
negative effect on research. For example, section 8 of the
ICH-E6 guideline1 lists dozens of documents as
“essential”. Compelling an investigator-initiated,
federally funded clinical study to create, maintain, and
archive all these documents (or justify an exception for
every one) diverts investigator teams away from science
towards administration. Many clinical trials are small
and lack the administrative support available in the
pharmaceutical industry. GCP has driven cost and
complexity to the point that “no clinician with his own
resources is now able to be the sponsor of a trial
involving more than a few patients”.17
Burdensome guidelines pose other problems.18 For
example, the ICH-E6 emphasis on monitoring and
auditing of data (sections 5·18 and 5·19) could be
misplaced.1 “intrusive, time-wasting audits that treat
those who organize trials and those who collaborate in
them as potential delinquents might well divert or
discourage clinical research workers from organizing as
many trials as they could otherwise have done . . . This
would mean that life-or-death questions will not be
answered as quickly or reliably as they should be.”19
As stated in ICH-E6, “This guidance should be
followed when generating clinical trial data that are
intended to be submitted to regulatory authorities.”
However, most human research does not have
regulatory aims. ICH-E6 draws a clear distinction
between the applicability of the guideline for regulatory
and non-regulatory research: “The principles . . . may
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Viewpoint
Problem Suggested solution
Title “Good Clinical Practice” is a misnomer Rename it “Good Clinical Research Practice”
Development process Use of the weakest approach to Revise with more evidence-based approach with
development of guidelines citation of relevant literature5
(informal consensus)3
Use of experts does not ensure best Update regularly
available evidence4
Contributors Authors not identified Revise with all important constituencies involved
Important constituencies omitted and identify authors and contributors7
from participation
Little trust from excluded researchers
and consumers6
Allocation Failure to recommend a procedure Revise after thorough search for relevant
concealment shown to reduce bias in randomised methodology literature
controlled trials8
Documentation More than 50 different documents Revise to identify truly necessary documentation
requirements deemed “essential” in section 8
Increased cost and complexity of research
Deterrent for small-scale, investigator-
initiated studies
Accessibility Not included in PubMed Publish in peer-reviewed journal indexed in
PubMed
Audience Intended as guidance for industry Revise to be more applicable to other research
Table: Problems with the GCP guideline
also be applied to other clinical investigations.”
Nevertheless, investigators of non-regulatory research
are increasingly being required to meet the documentary
standards of GCP.20 All research should be done well, but
GCP might not be the way to ensure it.
Solutions
One option would be to drop the GCP requirement for
research that is not destined for a regulatory agency.
Much of the documentation required by ICH-E6 has no
relevance to research validity or reliability. Given its
burdensome requirements, insistence on GCP for non-
regulatory research seems poorly advised.
A second solution would be to revise GCP. Although
ICH-E6 contains much useful material, its development
process was neither inclusive nor evidence-based.3
Moreover, ICH-E6 is obsolete and lacks a process for
regular updating. As a start, this guidance should be
renamed “Good Clinical Research Practice”. Then, the
guideline should be revised under the auspices of the
Institute of Medicine or another neutral organisation.
Representatives from all important constituencies
should participate,7 and the guideline should be made
more up to date, scientific, flexible, and simple.5
Collaboration with a wide range of clinical researchers
and determining the evidence-base for research
guidelines should be a priority. Present ICH efficacy
guidelines are uneven in content and style. Some read
like textbooks and contain useful advice (eg, ICH-E9:
Statistical principles for clinical trials). Others, such as
ICH-E6 (GCP), are proscriptive and bureaucratic.
This problem is acute. Commenting on the European
Directive on Implementing Good Clinical Practice,
which became effective in May, 2004, The Lancet has
forecast an “intolerable increase in red tape . . . publicly
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 Viewpoint
funded investigators are right to be very afraid indeed.”21
The UK Academy of Medical Sciences notes that “. . .
small scale exploratory studies may be driven out of the
UK and Europe by onerous enforcement of regulations
intended for another purpose . . . It is likely that smaller
centres will be unable to meet the costs and some
valuable innovative work will no longer take place in this
country.”22 Ironically, GCP might be impeding rather
than facilitating clinical research. Specifically, much
investigator-initiated research could disappear.
Collaborative, evidence-based efforts can and should
produce simpler and better research guidance.
Conflict of interest statement
We declare that we have no conflict of interest.
Acknowledgments
This Viewpoint was supported by Family Health International, although
the views expressed in the article do not necessarily reflect those of this
organisation or its funding agencies.
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