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Dr Robin J. Harman is a freelance pharmaceutical
and regulatory consultant based in Farnham, Surrey
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Despite being one of the most important elements of the data required
for the submission of a marketing authorisation application, until recently
there has been no pan-European legislation which governs how clinical
trials are conducted. Such legislation as existed was national legislation,
as a consequence of which there were significant differences in the requirements
within each EU member state as to how clinical trials should be undertaken
and controlled.
 An earlier article1 gave details of the concept of good clinical practice
(GCP) applied to clinical trials. However, GCP cannot be enforced by
legislation because its implementation in clinical trials is subject
only to a guideline, not a directive or regulation. The new Directive
2001/20/EC is therefore the first time that statutory controls have been
put in place to define the ways in which clinical trials are carried
out.
Reasons for the legislation
The primary EU legislation for the control of the authorisation of human
medicinal products is the Community Code (Directive 2001/83/EC). This
directive rationalised and standardised all pre-existing European legislation
relating to human medicinal products that had been passed since the
first such Directive 65/65/EEC in 1965. The code requires that marketing
authorisation applications should be accompanied by data containing
the particulars and documents relating to the results of clinical trials
carried out on a medicinal product. Part 4 of Annex I to Directive
2001/83/EC gives guidance on the documentation on clinical trials which
must be submitted, and also includes a requirement that all phases
of a clinical investigation should be designed, implemented and reported
in accordance with the principles of GCP.
As a result of the significant differences that have developed over the
years in the national requirements for carrying out clinical trials across
the EU, legislation has been introduced in an attempt to simplify and
harmonise the administration of clinical trials. Directive 2001/20/EC
establishes a clear and transparent procedure that is intended to allow
more effective co-ordination of trials within the EU by the regulatory
authorities.
Although the administrative processes are intended to be harmonised by
the introduction of the new directive, it was recognised at the outset
of its drafting that there would remain significant differences in the
way that clinical trials are actually conducted in each EU member state.
Had it been intended to harmonise clinical trial practices entirely across
the EU, the European Commission would have had to introduce a regulation,
which would automatically have been applicable in all member states.
Instead a decision was made to introduce a directive, which has to be
transposed into national legislation in each country. The new directive
should harmonise the administrative processes, but the underlying practice
and conduct of clinical trials will continue to vary across the EU.
Objectives and major change introduced
The full title of the legislation — Directive 2001/20/EC relating
to the implementation of good clinical practice in the conduct of clinical
trials on medicinal products for human use — explains its primary
purpose. After considerable negotiation and consultation within the European
Commission, agreement on the finalised version of the directive was reached
in February 2001, which was then published on 1 May 2001. An implementation
period of three years for the legislation was set, hence its provisions
must come into force in each EU member state by 1 May 2004.
Implementation in the UK The legislation is being implemented in the
UK by the Medicines for Human Use (Clinical Trials) Regulations 2003.
National implementation will significantly change the way in which clinical
trials within the UK are controlled. Under the existing UK system, control
is directed towards the supply of a medicinal product for a clinical
trial. Under the new system, it is the procedures which must be undertaken
to start and carry out a clinical trial and the manufacturing process
of any medicinal product(s) used in the trial (referred to as “investigational
medicinal products”, IMPs) that are controlled and monitored.
In addition, previously the person wishing to supply a medicinal product
for a clinical trial in the UK had to obtain a clinical trial certificate
(CTC) or a clinical trial exemption certificate (CTX). Instead, it will
be necessary to obtain a clinical trial authorisation from the regulatory
authority. The new controls also place on a legal basis the ethics committee
approval that must be obtained before starting a trial, which has resulted
in the creation of a new UK Ethics Committee Authority.
Protection of subjects One of the other major objectives of the directive
is that it sets out standards for the protection of subjects enrolled
in clinical trials and, in particular, incapacitated adults and minors.
In effect, the directive is intended to protect participants in trials
by the introduction of GCP principles into the regulation and conduct
of clinical trials.
Main points of the directive
Directive 2001/20/EC has a particularly wide scope and applies to every
clinical trial on medicinal products, whether sponsored by the pharmaceutical
industry, by government, by research organisations, by a charity or
by a university. It emphasises that the basis for the conduct of clinical
trials is the protection of human rights and the dignity of human beings,
as reflected in the Declaration of Helsinki. Before a clinical trial
is carried out, the potential risk to participants must have been assessed
by carrying out animal toxicological experiments, by screening undertaken
by ethics committees and by the drug regulatory authority, and by compliance
with the rules on the protection of personal data.
Clinical trials involving children The situation of clinical trials
conducted in children is more complicated. It is essential that trials
to develop medicinal products for children are undertaken whenever possible,
but with the clear recognition that children represent a vulnerable population.
They are at a different stage of development and have different physiological
and psychological characteristics from adults. As a result, their response
to the administration of particular medicinal products will inevitably
be different from that of an adult. One of the most important classes
of medicine available for children, and in which clinical trials are
essential before their use, are vaccines used against childhood diseases.
The directive lays down the criteria for the protection of children in
clinical trials.
Problems in giving informed consent The directive emphasises the need
for those who are incapable of giving informed consent to their participation
in a trial to be given special protection. Moreover, no such person can
be included in a trial if the same results could be obtained using a
person who can give their informed consent to their participation. Those
unable to give their informed consent should only be included when it
is likely that the administration of the drug would be of direct benefit
to them as individuals.
For adults who are unable to give their informed consent (eg, those suffering
from dementia or those who are psychiatric patients), the directive imposes
even stricter controls. As with trials in children, there must be seen
to be a clear potential benefit for the individual participating in the
trial. In addition, if their inclusion is deemed to be essential, the
written consent of the patient’s legal representative must be obtained
before starting any trial, and this must be obtained in co-operation
with the treating doctor.
Since one of the primary objectives of the legislation is to provide
protection for participants in clinical trials, the directive also requires
that obsolete or repetitive tests should not be carried out at any time.
The legislation recognises that the harmonisation of the technical requirements
for the registration of medicinal products under the ICH process will
help to reduce the likelihood of repetitive tests being carried out in
different global regions.
Administrative procedures A new European database is to be established
in which information on the content, and start and finishing dates of
a clinical trial are to be recorded. The data are to be made available
to the regulatory authorities in member states in which the trial is
taking place and to all other member state regulatory authorities.
As mentioned above, there are currently significant differences in the
ways in which member states carry out the control and conduct of clinical
trials in their own territories. This has led to delays and complications,
preventing the effective conduct of clinical trials throughout Europe.
The administrative provisions for clinical trials are therefore being
harmonised and simplified in order to create a clear and transparent
procedure across the EU, thereby enhancing the co-ordination of authorisation
of trials by the regulatory authorities.
In theory, the application to begin a clinical trial submitted to an
ethics committee and to a regulatory authority should be deemed to be
approved unless a definite negative response has been received from one
of those two bodies. It is only if there has been significant interaction
between the approving bodies and the applicant on various aspects of
the clinical trial application that a formal, explicit authorisation
would be deemed to be necessary.
Investigational medicinal products Investigational medicinal products
should be prepared in accordance with the principles of good manufacturing
practice (GMP) with appropriate labelling of such products.
The directive recognises that non-commercial clinical trials frequently
take place without the participation of the pharmaceutical industry and
therefore without their considerable
resources to underpin the trial activities. Such trials usually take
place with medicinal products that are already authorised and which are
therefore manufactured in accordance with the principles of GMP. The
trials are usually undertaken to investigate further the indications
already approved for a particular medicinal product. It is proposed within
the directive that there should be simplified labelling of investigational
medicinal products for such trials which are to be laid down in the GMP
guidelines for investigational medicinal products.
Conformity with good clinical practice All clinical trials must be undertaken
to the standards of good clinical practice (GCP), with the corresponding
need for the data collected during the trial to be properly recorded
and reported in order to justify the involvement of human subjects in
the trial. Moreover, any individual participating in a clinical trial
must give informed consent to the scrutiny of personal data by the regulatory
authority and by the ethics committee, and be reassured that the data
are treated in a strictly confidential manner.
Scope of the directive
The directive for the first time includes not only clinical trials involving
patients who are intended to benefit from the course of treatment administered,
but also those involving healthy volunteers (Phase I trials). In effect,
all trials that are undertaken with a medicinal product are subject
to the terms of the directive, which includes both commercial and non-commercial
research. This is a major change for the UK, although in implementing
the requirement, the UK will be brought more into line with the current
situation in almost all other EU member states.
A number of definitions are given in the directive (Panel 1). Several
issues arise from the definitions given.
Panel 1: Definitions contained in Directive 2001/20/EC
Clinical trial Any investigation involving human subjects intended
to discover or verify the clinical, pharmacological or pharmacodynamic
effects of one or more investigational medicinal products, or to
identify any adverse reactions to one or more investigational medicinal
product, or to study absorption, distribution, metabolism, and excretion
of one or more investigational medicinal product with the object
of assessing their safety and efficacy. This includes clinical trials
carried out in either one site or multiple sites, whether in one
or more than one member state.
Multi-centre clinical trial A clinical trial conducted according
to a single protocol but at more than one site, and therefore by
more than one investigator, in which the trial sites may be located
in a single member state, in a number of member states, or in member
states and third countries.
Non-interventional trial A study where the medicinal products are
prescribed in the usual manner in accordance with the terms of the
marketing authorisation. The assignment of the patient to a particular
therapeutic strategy is not decided in advance by a trial protocol
but falls within current practice, and the prescription of the medicine
is clearly separated from the decision to include the patient in
the study. No additional diagnostic or monitoring procedures shall
be applied to the patients and epidemiological methods shall be used
the analysis of collected data.
Investigational medicinal product A pharmaceutical form of an active
substance or placebo being tested or used as a reference in a clinical
trial, including products already with a marketing authorisation
but used or assembled (formulated or packaged) in a way different
from the authorised form, or when used for an unauthorised indication,
or when used to gain further information about the authorised form.
Sponsor An individual, company, institution or organisation which
takes responsibility for the initiation, management or financing
of a clinical trial.
Investigator A doctor or person following a profession agreed in
the member state for investigations because of the scientific background
and the experience in patient care it requires. The investigator
is responsible for the conduct of a clinical trial at a trial site.
If a trial is conducted by a team of individuals at a trial site,
the investigator is the leader responsible for the team and may be
called the principal investigator.
Investigator’s brochure A compilation of
the clinical and non-clinical data on the investigational medicinal
product or products which are relevant to the study of the product
or products in human
subjects.
Protocol A document that describes the objectives,
design, methodology, statistical considerations and organisation
of a trial. The term “protocol” refers
to the protocol, successive versions of the protocol and protocol
amendments.
Subject An individual who participates in a clinical trial as either
a recipient of the investigational medicinal product or a control.
Informed consent The decision, which must be written, dated and
signed, to take part in a clinical trial, taken freely after being
duly informed of its nature, significance, implications and risks,
and appropriately documented, by any person capable of giving consent
or, where the person is not capable of giving consent, by his or
her legal representative. If the person is unable to write, oral
consent in the presence of at least one witness may be given in exceptional
cases, as provided for in national legislation.
Ethics committee An independent body in a member state, consisting
of health care professionals and non-medical members, whose responsibility
it is to protect the rights, safety and well-being of human subjects
involved in a trial and to provide public assurance of that protection
by, among other things, expressing an opinion on the trial protocol,
the suitability of the investigators and the adequacy of facilities,
and on the methods and documents to be used in to inform trial subjects
and obtain their informed consent.
Inspection The act by a competent authority of
conducting an official review of documents, facilities, records,
quality assurance arrangements
and any other resources that are deemed by the competent authority
to be related to the clinical trial and that may be located at the
site of the trial, at the sponsor’s or contract research organisation’s
facilities, or at other establishments which the competent authority
sees fit to inspect.
Adverse event Any untoward medical occurrence in a patient or clinical
trial subject administered a medicinal product and which does not
necessarily have a causal relationship with this treatment.
Adverse reaction All untoward and unintended responses
to an investigational medicinal product related to any dose
administered.
Serious adverse event or serious adverse reaction Any
untoward medical occurrence or effect that at any dose results in
death, is life-threatening, requires admission to hospital or
prolongs existing hospital stay, results in persistent or significant
disability or incapacity, or is a congenital anomaly or birth
defect.
Unexpected adverse reaction An adverse reaction,
the nature or severity of which is not consistent with the applicable
product information
(eg, investigator’s brochure for an unauthorised investigational
medicinal product or Summary of Product Characteristics for an authorised
product). |
A “clinical trial” is any activity in which the safety and
efficacy of a medicinal product is being assessed. Under these circumstances,
a clinical trial authorisation is required. For any product that is used
in a clinical trial, either as a test product or as a reference product,
a manufacturing authorisation is also required.
“
Non-interventional trials” are excluded from the definition of
a clinical trial. In such trials a medicinal product is usually administered
in a way which falls within current practice and there is no separation
of patients into reference or placebo groups before administration. Moreover,
no additional diagnostic or monitoring procedures are applied to the
patients. In other words the patient is receiving the same treatment
as he or she would do under normal clinical care. Should this remain
the case, the study is classed as “non-interventional”.
A “sponsor” is any entity which takes responsibility for
starting, managing, and/ or financing a clinical trial. In the UK, many
clinical trials, and especially Phase I studies, have been carried out
in collaboration between universities, the National Health Service, research
councils and charities. In such cases, the sponsor would be the individual
body that takes on this ultimate responsibility for the trial. It is
necessary for those involved in the conduct of the trial to determine
and to agree upon who is the sponsor for a particular trial and for that
nominee to be notified to the regulatory authorities.
Protection of clinical trial subjects
It is essential that a clinical trial is only undertaken when there is
considered to be a possible benefit for the individual taking part
in the trial and for future patients. The expected therapeutic and
public health benefits should justify the risks, and the assessment
of this criterion is carried by an ethics committee and by the regulatory
authority. The clinical trial is also permanently monitored to ensure
the continued benefits justify the risks.
It is essential that the participants in the trial have been fully informed
of its objectives, the risks entailed and possible inconvenience in their
participation. Participants must also have been advised of their right
to withdraw from the trial at any time without prejudice. If a participant
is unable to give informed consent, the same explanation should be given
to his or her legal representative. If a participant is not able to write
his or her informed consent, oral consent may be obtained as long as
it is in the presence of at least one witness, whose role should then
be recorded.
The investigator and sponsor should ensure that insurance or indemnity
has been obtained to cover their liabilities for the clinical trial.
It is also essential that the care of the subjects taking part in the
trial is maintained under an appropriately qualified medical doctor.
Clinical trials involving minors
The legislation recognises the difficulties in obtaining informed consent
from minors, drawing particular attention to the capacity of understanding
displayed by individuals about what is being proposed by their participation
in the clinical trial. If a young person understands what is being proposed,
but refuses to participate or requests to be withdrawn from the clinical
trial at any time, this decision must be respected. Moreover, no incentives
or financial inducements should be given to a child, other than compensation.
One of the other important aspects of the legislation is that there should
be some direct benefit for the group of patients, and the trial should
only be carried out when it is essential to validate data obtained in
clinical trials where participants have been able to give their informed
consent. In addition, the clinical trial and its objectives should relate
directly to the condition from which the young person is suffering, or
it must be such that the trial can only be carried out on this particular
age group.
Clinical trials in all age groups should be undertaken and designed so
as to minimise the level of pain, discomfort, fear and other risks. These
requirements are especially important when it comes to undertaking clinical
trials in children and young people.
Clinical trials involving those unable to give informed consent
The inability to be able to give informed consent to participation in
a clinical trial can often arise because of serious or life-threatening
conditions, or because the ability of an individual to understand what
is being requested is severely restricted. Whenever possible, as much
information as is likely to be understood should be given to an incapacitated
adult. Again, as with young patients, should there be any indication
that the individual does not want to participate in the trial, this
should be respected.
The informed consent of an incapacitated adult’s legal representative
must be obtained in place of that of the participant. The consent given
by the legal representative must represent what the individual would
presumably have decided had he or she been able to make the choice for
themselves.
As in the case of clinical trials on minors, it is vital that the interests
of the patient always prevail over those of science and society in general.
The role of the ethics committee in assessing the involvement of an incapacitated
adult is vital in ensuring that the rights and interests of the individual
are always respected and maintained.
The legal representative may be somebody classed as a “personal
legal representative” who is chosen as a consequence of the relationship
with the potential participant in the clinical trial. This might be a
member of the close or extended family or someone who can demonstrate
a close personal relationship with the individual concerned. By comparison,
if no one appropriate can be identified for that purpose, a “professional
legal representative” should act for the individual.
In some cases, potential participation in a clinical trial may arise
at extremely short notice (eg, after cardiac arrest or following a severe
head injury). It can often be difficult to locate an appropriate person
to act as a personal legal representative. The likelihood of this situation
arising would previously have been identified in the protocol submitted
to an ethics committee, and the procedure to be followed would have been
approved by the ethics committee before starting the clinical trial.
The directive does not seek to prevent emergency research being carried
out.
The role of ethics committees
For the first time, the role of an ethics committee has been brought
under statutory provisions. The function of an ethics committee is
to provide an opinion before a clinical trial starts having been given
details of the following particulars:
• The relevance of a clinical trial and the trial design
• Evaluation of the expected benefits and risks
• The protocol
• Suitability of the investigator and supporting staff
• The investigator’s brochure
• The quality of facilities available
• The process for obtaining informed consent and the alternative procedures
for doing so on behalf of those incapable of giving informed consent
• Details of any indemnity or compensation in the event of injury or
death attributable to the clinical trial
• Insurance to cover the liability and the investigator and sponsor
• Details of payments to be made to investigators and participants in
the trial
• Arrangements for the recruitment of clinical trial subjects
Only if the opinion of the ethics committee on all the above points
is favourable will the trial be permitted to start. The legislation requires
that the decision from the ethics committee must be supplied within 60
days of the date of receipt of the application. If the ethics committee
requires further information to make a final judgement as to its opinion,
the time taken for that further information to be supplied by the applicant
is not included in the 60-day schedule. For certain products (eg, medicinal
products for gene therapy and somatic cell therapy, or products containing
a genetically modified organism), the ethics committee is allowed 90
days to consider its opinion. A further 90 days may be allowed for the
opinion of the ethics committee if it considers it necessary to consult
further to consider such trials.
To ensure the effective functioning of ethics committees, a new UK Ethics
Committee Authority (UKECA) has been created to establish, recognise
and monitor ethics committees. The executive procedures of the UKECA
are carried out by the Central Office of Research Ethics Committee (COREC).
Ethics committees opinions The legislation
has established a procedure to obtain a
single opinion for multi-centre trials. If all the sites for the multi-centre
trial are located within the UK, an ethics committee application is directed
to the committee located within or covering an area in which the chief
investigator for the trial is based. If the locations of a multi-centre
trial are in more than one EU member state, each member state is required
to give an opinion on the acceptability of the clinical trial.
Starting a clinical trial
Before any clinical trial can start, the sponsor must submit a valid
request for an authorisation to the regulatory authority of the member
state in which the trial is to be conducted. In the UK, the competent
authority is the Medicines and Healthcare products Regulatory Agency
(MHRA). If the MHRA refuses an application for a clinical trial authorisation,
it can be referred to the Committee on Safety of Medicines (CSM) and
the Medicines Commission. At the same time as the application to the
MHRA, a favourable opinion must be received from an ethics committee
(see above). The legislation describes three classes of medicinal product
for the purposes of clinical trial authorisations, with varying time
schedules for approval of the authorisation:
• General medicinal products
• Medicinal products for gene therapy and somatic cell therapy
• Medicinal products with special characteristics (eg, biological products
of human or animal origin)
For general medicinal products the time limit for assessments of clinical
trial authorisation application must not exceed 60 days. Extensions are
permissible for the two classes of medicinal products other than general
medicinal products.
Conduct of clinical trials
It may be necessary for a sponsor to make amendments to the protocol
for the clinical trial. If such amendments are deemed to be “substantial”,
the competent authority and the ethics committee must be notified in
writing. The ethics committee has a maximum of 35 days upon receipt
of the proposed amendments to give its opinion. Amendments to the protocol
can also be made by the competent authority, but before doing so it
must give at least 14 days’ notice of the proposed amendments
to the sponsor.
“Substantial” amendments to a clinical trial or authorisation
would include the following:
• The safety and personal integrity of the subjects of the trial
• The scientific values of the trial
• The conduct and the management of the trial
• The quality or safety of an investigational medicinal product used
in the
trial
Amendment to the clinical trial authorisation may also be required in
the event of the development of significant hazards to the health and
safety of subjects that require the sponsor to undertake urgent safety
measures. Such actions can be undertaken by the sponsor without prior
notification to the competent authority, but written notification must
follow within three days of those actions.
At the end of the clinical trial, the sponsor must notify the competent
authority and the ethics committee that the trial has ended within 90
days of its completion. If the trial has had to be terminated early,
notification to the regulatory authority must take place within 15 days
of the end of the trial and the reasons for the early termination clearly
explained.
Exchange of information between regulatory authorities
A new EU clinical trial database is to be established whose access is
restricted to the regulatory authorities of EU member states, the European
Agency for the Evaluation of Medicinal Products (EMEA) and the European
Commission. This database stores the details of the following aspects
of clinical trials currently being undertaken within the EU:
• Extracts from the requests of authorisation
• Any amendments to the request for authorisation
• Amendments to the protocol
• A favourable opinion of the ethics committee
• The declaration at the end of the clinical trial
• Details of last inspections for compliance with GCP
Although concerns have been expressed by pharmaceutical companies about
the security of such information, the EU database is intended to ensure
the confidentiality of all data.
Investigational medicinal products
Manufacture and import All medicinal products which possess a marketing
authorisation must be manufactured according to the standards of good
manufacturing practice (GMP) and under the supervision of a Qualified
Person. Likewise, Directive 2001/20/EC requires that investigational
medicinal products (IMPs) must be manufactured according to a separate
manufacturer’s authorisation. In effect, a pharmaceutical company
must possess two manufacturer’s authorisations: one for its authorised
medicinal products and one for its IMPs. The IMPs manufacturer’s
authorisation covers the manufacture, assembly and/or importation of
an IMP. To obtain an authorisation, it is necessary for the manufacturer
to comply with the principles and guidelines of GMP as laid down in
Directive 91/356/EEC.
If IMPs are imported from third countries outside the EU, the importer
must also possess an IMP manufacturer’s authorisation. Likewise,
where an IMP is manufactured in the UK and is intended to be exported
to third countries for use in a clinical trial, the UK manufacture must
be in possession of an IMP manufacturer’s authorisation.
Certain exemptions apply to the requirement to hold an IMP manufacturer’s
authorisation. It is not required if the IMP is repackaged or changes
are made to the packaging in a hospital or health centre by a doctor
or pharmacist and the IMP is to be used in that hospital or health centre.
Equally the reconstitution of IMPs (eg, dissolution or dispersal of the
product, its dilution, or mixing with another substance) before administration
does not constitute manufacture, and such activities would not be subjected
to an IMP manufacturer’s authorisation.
The Qualified Person has to ensure that the appropriate test and controls
have been carried out on the IMP and has to sign for each batch that
this has been done. A register of manufacturing must be maintained and
entries made into the register as soon as possible after each batch has
been manufactured and before it is released for use in the clinical trial.
The qualifications of the individual chosen to act as a Qualified Person
must be submitted in the application for an IMP manufacturer’s
authorisation. The Qualified Person must be a member of the Institute
of Biology, the Royal Pharmaceutical Society of Great Britain or the
Royal Society of Chemistry. The role of the Qualified Person is in effect
the same as that required for the control and release of batches of authorised
medicinal products.
Labelling The labelling requirements for IMPs are detailed in Annex
13 of the GMP guidelines, Directive 91/356/EEC. If the product is not
correctly labelled in accordance with these requirements, it is a criminal
offence for a sponsor to sell or supply or procure the sale of or supply
of an IMP for a clinical trial.
Inspection procedures
The maintenance of the standards of GMP and GCP are critical for the
safe and effective use of IMPs. To ensure their maintenance, inspectors
are appointed by the regulatory authorities to visit the sites of clinical
trials and the manufacturing sites of the IMP. In addition any laboratory
used for the analysis of clinical trial data and the sponsor’s
premises may also be subject to inspection.
Inspections are carried out by a competent authority of the member state
in which the clinical trial or manufacture occurs, and the result of
that inspection is notified to the other interested parties (ie, other
competent authorities and ethics committees) in the clinical trial. Doing
so helps to minimise the potential for duplication of inspections by
individual member states. If the manufacturing site or a clinical trial
location is in a third country outside the EU, Directive 2001/20/EC provides
for inspection by a member state competent authority to be undertaken
by appropriately qualified EU inspectors. The inspection report for all
inspections is made available to the sponsor and to other member states,
to ethics committees, and to the EMEA, should they so request.
Notification of adverse events
Both serious adverse events and suspected unexpected serious adverse
reactions (SUSARs) during a clinical trial must be notified as they
occur to the competent authority. In addition, the sponsor must also
provide an annual list of all serious adverse events (expected and
unexpected) and a report of the safety of subjects participating in
the trial.
Some adverse events will have been anticipated before starting the trial
and their details given in the protocol or investigator’s brochure.
However, those not so listed must be notified by the sponsor to the competent
authority immediately and followed up by detailed written reports. Such
reports must be identified by unique code numbers assigned to identify
the individual subject. If a death occurs during the course of a clinical
trial, the investigator must supply the sponsor and the ethics committee
with any additional information they require.
SUSARs that are fatal or life-threatening must be recorded by the sponsor
and reported as soon as possible to the competent authority and to the
ethics committee, and in any case no later than seven days after the
event has been reported to the sponsor. If the SUSARs are not fatal or
life-threatening, the report to the competent authority and the ethics
committee must be made within 15 days by the sponsors. The investigators
at all sites of the clinical trial with the IMP must also have been notified
by the sponsor of the SUSAR.
An EU pharmacovigilance database is to be established for recording all
SUSARs notified by sponsors to regulatory authorities. All member states
will have access to the pharmacovigilance database, but not the sponsors
of clinical trials. Other regulatory authorities, the EMEA, and the European
Commission will also have access to the database.
Fees payable
The regulatory authority charges fee for the assessment of pharmaceutical,
preclinical and medical data for applications for clinical trial authorisations.
The fees reflect the time and resources necessary to complete the assessment
of the application. An annual service fee is also charged by the regulatory
authority to cover good administrative activities and enquiries related
to each programme of trials with an IMP.
Fees are also payable for applications submitted for IMP manufacturer’s
authorisations, which cover the application, variations and inspections
together with an annual service fee during the lifetime of the manufacturer’s
authorisation. The fee for inspection of a manufacturer is based upon
the size of the company inspected as determined by the number of relevant
employees. Fees for GCP inspections have also been introduced by the
regulatory authority. Reference
1. Harman RJ. The concept and implementation of good clinical practice
in trials. Pharm J 2003;270:
653–7. |
