One year on: what has been the impact of the clinical trials directive?
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The impact of the legislation on clinical trials
was reviewed before a large audience of representatives from the
pharmaceutical industry and the National Health Service at a recent
meeting. Joseph Chamberlain reports
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This one-day update symposium was organised by
the Joint Pharmaceutical Analysis
Group in association with the
Academy of Pharmaceutical Scientists and the Royal Pharmaceutical
Society Hospital
Pharmacists Group on 19 May
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Impact on medicines regulators
After a background paper on the development and the requirements of
the clinical trials directive (CTD) by Brian Davis of the Medicines and
Healthcare products Regulatory Agency, the feedback from the regulators
was presented. Bronwyn Phillips, an MHRA inspector, explained that
from 1 May 2004 the voluntary programme of inspection had ceased.
Around
175 applications have since been received, the majority (120) from
existing licensed sites.
An important aspect of inspections has been the assessment of the
Qualified Person (QP). Transitional arrangements are used by about
40 per cent
of applicants but such arrangements will apply only until May 2006.
QPs must not only have the appropriate qualifications, as laid out
in the
directive, but must have demonstrated competence to carry out the duties.
Prioritising inspections has been based on risk, with first-time applicants
and applicants making sterile products being high on the list. Inspections
are announced and are concerned mainly with facilities. Key issues
uncovered included poorly developed quality systems, inadequate facilities,
inadequate
validation, poorly defined QP responsibilities, insecure chain maintenance
in transit and on site, poor practices in the design and printing of
labels, careless handling of randomisation codes, and a failure to
address issues surrounding transmissable spongiform encephalopathies.
Ms Phillips
gave numerous specific examples of major problems encountered during
inspections, including a case where the management blamed lack of training
for a deficiency when it was apparent that it was the system that was
at fault. Nevertheless Ms Phillips concluded that the UK industry was
generally in good shape. There was still lots to learn and it is important
to maintain an effective dialogue with the regulatory authorities.
Elaine Godfrey, of the MHRA clinical trials unit, provided the experiences
of an assessor. The implementation of the CTD represented the biggest
change in clinical trials legislation since the introduction of the
clinical trials exemption (CTX) more than 20 years ago. The changes
occurring
in the UK represented the difference between the previous legislation
and the current legislation and were, therefore, not the same as those
occurring in other member states which previously had different systems
of regulating clinical trials. Important changes have been that healthy
volunteer trials are now regulated with authorisation of the trial
rather than the supply of a product. Good manufacturing practice, good
clinical
practice, labelling and the system of ethics committees are now better
integrated. Regulation of human volunteer trials by the MHRA is new
but initial concerns about delays resulting from this change have not
been
realised. The MHRA
consulted widely and the new process is in fact speedier than that
under the ethics
committees.
Additionally, under the previous legislation approximately 10 per cent
of CTX applications were refused, whereas under the new legislation
grounds for non-approval (GNA) at the appropriate decision point are
only 1 to
2 per cent. Applicants receiving GNA letters receive these for safety
reasons and most GNA applications are approved after further information
has been provided. Safety issues may arise from the product or the
protocol, and are due to a lack of discussion of potential issues.
Major problems
included data not summarised or incomplete, applications not page-numbered
or not indexed, over-use of appendices, and inappropriate font size.
Sometimes the supporting scientific data were incomplete, the study
rationale was unclear, the data package did not comply with guidelines,
or there
was no integrated safety summary. The new requirements were often overlooked,
labelling was not presented in the format to be used or even not presented
at all; there may have been no QP statement on GMP, or there was no
copy of the marketing authorisation (MA) for the investigational medicinal
product (IMP) or equivalent. The assessor would like to see clearly
presented
applications with summarised data, which follow commission guidance
and are structured according to the common technical document. All
necessary
components from the commission guidance must be included with no unasked-for
documents added. Only substantial amendments should be submitted. After
a gestation of 10 years, the implementation of the directive is now
complete. It is no longer permissible to use the previous forms of
documentation,
no matter how beautifully presented. The future has arrived, concluded
Dr Godfrey.
Impact on industry
Robert Smith, of Genzyme, presented the experiences of an international
biotech company manufacturing clinical trial supplies. An important
aspect of the new directive is the requirement for a Qualified Person
to be legally responsible for certifying and releasing clinical trial
materials. The QP is involved in many aspects of the clinical trial
process, from visiting third country manufacturing sites to giving
advice to a number of different professionals on a whole range of topics.
The recently approved good clinical practice directive also impacts
on the manufacturers of clinical trial materials. As well as this directive,
Annex 19 on “Retain and reference samples” also may affect
the samples that clinical trial material manufacturers may have to keep
in the future. Finally, there are International Conference on Harmonization
guidelines that are being worked on that in the future will affect the
manufacture of clinical supplies.
Philip Butson, of GlaxoSmithKline, had distilled the views of many colleagues
to give an industrial perspective of the effect of the clinical trials
directive. Experiences with inspections suggest they are primarily general
inspections of quality systems and good manufacturing practice, with
the specifics of the investigational new product forming a part.
The use of published information to identify the main areas where the
MHRA has historically identified issues is to be encouraged. Mr Butson
commented that it made sense to carry out self-inspections of these quality
indicators, such as deviations, out-of-specification laboratory results,
batch rejections, customer complaints and recalls. Inspections of IMP
activities may start with a high level question such as determining how
clinical requirements are determined and met, then move on to look at
the components of the answer in more detail.
Systems in place to prevent mix-ups are particularly scrutinised because
blinding of placebos and comparators means products not distinguishable
by appearance must be well controlled.
Impact on the health service
Clinical trials form part of the work
of 96 per cent of NHS hospitals |
The directive has had a huge impact on the NHS because 96 per cent
of all hospitals are involved in clinical trials in some form, said Paul
Forsey, of Guy’s and St Thomas’ NHS Trust. Most effect
is on non-commercial trials which, before May 2004, were run under
the DDX (doctors and dentists exemption) and CTX (clinical trials exemption)
schemes. About 20 NHS sites have applied for an MA. The directive definition
of manufacture is helpful when assessing whether a trial fits under
the directive or whether the activity is exempt from the need for a
marketing authorisation (MA). Studies that have purely physiological
outcomes and are not assessing safety or efficacy are considered to
be outside the scope of the directive. Exemptions in terms of reconstitution
or assembly do not require the need for an MA but there are a number
of areas requiring clarification. The role of the Qualified Person
needs to be seen as releasing material within the context of the trial,
which includes all aspects, including the final link to the patient.
The QP is involved from the initial discussions with the investigator
or sponsor, said Mr Forsey. There is a need to develop a generic NHS
QP specification in terms of essential experience and qualifications
required. There will be a requirement to link this to the Knowledge
and Skills Framework. When designing packaging and labelling for IMPs
the process of supply to the patient needs to be taken into consideration
as this can significantly affect the outcome. There is a need to provide
some good practice guidance to support professional judgements. One
year on, we do have clarification on a number of issues especially
with regards defining what is covered by the directive and in what
circumstances an MA (IMP) is not required. However, further work is
required but it is imperative that local interpretations are shared
where possible to promulgate best practice. Where sufficient support
and expertise exists there is no reason why the requirements under
the directive should be a barrier to undertaking non-commercial trials.
V’Iain Fenton-May, of St Mary’s Pharmaceutical Unit, Cardiff,
reviewed experience in the NHS and Europe, particularly with reference
to non-commercial clinical trials. Activities associated with hospital
clinical trials (both commercial and non-commercial) include dispensing,
preparation, labelling, blinding, organising and manufacturing. The directive
applies equally to commercial and non-commercial trials but we need sponsors
for doctor-led trials. There is now an added cost, not just that of registration
fees, but the expense and difficulty in obtaining insurance on anything
with a clinical trials label attached. There is also a perceived increase
in bureaucracy as well as a lack of understanding among colleagues. Real
difficulties are foreseen with the successful establishment of QPs.
Non-commercial trials are still in the transition between DDX and clinical
trials authorisation, and more training is needed in all spheres. Mr
Fenton-May also pointed out the particular difficulties with commercial
trials, including the real possibility of confusion in labelling of dispensed
items. There will need to be a move to realistic costing and support.
The relationship on both sides needs to mature.
Before 2003 the perception in European hospitals was that there were
few non-commercial trials, said Mr Fenton-May. Most EU countries believed
that the laws already covered the needs of the directive, and that the
pharmacist
was a QP by right and needed no additional training or experience. Although
by 2005 it was recognised that there are indeed non-commercial trials
in Europe, and that there was a need for a MA (IMP) and therefore inspections
by a competent authority, Europeans still do not seem to recognise the
special duties and attributes of the QP.
Implementation of the directive in
the Netherlands
Helena van den Dungen, of the inspectorate of health care, Ministry
of Health, the Netherlands, undertook to describe experiences with implementation
of the directive in Europe but had to confess that, at the time of
the
meeting, the EU clinical trials directive has not yet been implemented
in the Netherlands legal system, making a description of its local
impact premature. However, good clinical practice has long-been formally
implemented
in the Dutch legislation and full clinical trials legislation covering
all clinical trials was implemented in 1999 as the law on medical research
(Wet Medisch Onderzoek).
The WMO ensures protection of subjects by identification of responsibilities,
considering informed consent particularly in trials with minors and
incapacitated subjects, regulation of ethics committees and ethical
review (including
a single ethics opinion for multi-centre trials), and regulation of
insurance. It already contains many of the requirements of the EU CTD. Important new aspect
The most important new aspect is the installation of a competent authority
to which clinical trials are notified. In addition, development of
an electronic database, where notification to the competent authority
and request for approval by the ethics committee can be made simultaneously,
is well advanced. Implementing activities have been pre-empted by the
regulatory authorities, for example, through the installation of a
ministerial working group where all involved parties are represented.
These would include competent authorities, ethics committees, inspectorate,
industry, academic hospitals, contract research organisations and biotech
companies. This working group has been active in organising an information
platform, channelling questions and identifying potential problems. In
addition a manual has been developed to explain the new additions to
the legislation and further define the standards.
The Dutch inspectorate has conducted statutory inspections of clinical
trials since 1993. Inspections have been carried out in the Netherlands
as well as in other EU member states and in third countries.
The inspections have been conducted as the result of national requests
(local applications and “for cause” as well as those under
the mutual recognition procedure), requests by other EU member states,
or instigation by the inspectorate itself.
The Dutch inspectors have been actively involved in the European Medicines
Agency Inspection Services GCP inspectors working group since the establishment
of the group in 1997.
Panel discussion
In a final session the speakers for the day faced a lively set of questions
from the audience. Feelings towards the new directive were positive.
Brian Davis said that people are becoming involved in it and are recognising
that the existing systems are not adequate to protect the patient and
ensure quality new information. The directive has focused a lot of
attention and in general, the environment within Europe is going to
be much improved as a result of this directive. V’Iain Fenton-May
thought that if we had had proper clinical trials 20 years ago then
perhaps we would not have seen some of the product withdrawals we are
seeing today. The new legislation was much welcomed.
A full report on the discussion session can be found on the website
of the Joint Pharmaceutical Analysis Group at www.jpag.org |
The
Pharmaceutical Journal