ABPI Guidelines for Phase 1 Clinical Trials (PDF

Administration of doses
The number of subjects dosed on any one occasion,
and the interval between dosing individual subjects
and cohorts of subjects, will depend on the IMP, its
route of administration, and the type of trial. For
example, only one subject must be given an active
IMP at the very first administration of a higher-risk IMP.
And if the route of administration is intravenous, the
dose should be given by slow infusion, perhaps over
several hours, rather than by rapid injection, unless
there is a good reason for that method. In contrast, if
the IMP is of low risk and the route of administration
is oral, cohorts of subjects can be dosed on the same
occasion, and at short intervals, say every 5-10
minutes.
Facilities and staff
First-in-man trials of an IMP are regarded as higher risk
than later phase 1 trials. But, the risk during transition
from pre-clinical studies to the very first-in-man trial
may be no higher than it is during other transition
trials, such as from single to multiple doses, from
young to elderly subjects, and from administration of
the IMP alone to giving it with established medicines
during interaction trials. Sponsors must place their
trials of an IMP - especially a first-in-man trial and
other transition trials - with phase 1 units, including
their own, whose staff, premises and facilities
(Section 9) match the level of risk of the IMP.
Furthermore, investigators must not take on trials
of an IMP for which they do not have adequate
experience or training (Section 10).
The investigator must assess the risk of harm, by
reviewing the protocol, investigator's brochure, IMP
dossier, CTA application (Section 12) and, as required
by the Declaration of Helsinki, 34 any relevant medical
and scientific literature. Also, the investigator must
weigh the foreseeable risks and inconveniences against
the expected benefits for the individual subject, and for
future subjects with the target disease. Finally, the
investigator must explain and justify any risks in the
information leaflet for trial subjects (Section 11) and in
the REC application (Section 13).
Procedures
Non-invasive trial procedures should be used
whenever possible. If invasive procedures - such as an
arterial cannula, a biopsy or an endoscopy - are used,
they must be done or supervised by someone skilled in
the procedure.
Subjects
The decision as to whether a phase 1 trial should be
done in healthy subjects or patients should be made
on a case-by-case basis. Most IMPs can and probably
should be tested first in healthy subjects. Compared
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with patients, healthy subjects are easier to find, more
robust, free of other medicines, more likely to respond
uniformly, and better at completing long and complex
trials. Also, healthy subjects tolerate IMPs better than
patients. 35 On the other hand, for some IMPs, obese
subjects or subjects with high serum cholesterol may
be more suitable than truly healthy subjects. But,
some IMPs - such as cancer therapy and most types of
gene therapy (Section 16) - should be given only to
patients with the target disease (Section 11).
6: Safety record of phase 1 trials
Reviews of the safety of phase 1 trials show that they
have a good safety record. 34-35 Overall, the incidence
of serious adverse events related to the IMP was about
0.02%. However, some healthy subjects have died.
A man died of cardiac arrest after taking an IMP in a
trial in Ireland in 1984. When he was screened for the
trial, he did not declare that he had recently been
given a depot injection of an anti-psychotic
medicine. 38 A woman died after receiving a high
dose of lidocaine - a widely used local anaesthetic -
to prevent discomfort from endoscopy in a trial in the
USA in 1996. 39 She was discharged soon after the
procedure and died at home. Another woman with
mild asthma died of lung damage after inhaling
hexamethonium in a trial in the USA in 2001. 40
Hexamethonium is an old medicine - given by
injection to treat conditions other than asthma -
and is now rarely if ever used. Lung toxicity of
hexamethonium was first reported many years ago. 41
These cases show that established medicines as well as
IMPs have the potential to harm subjects in phase 1
trials. Also, they highlight the need to:
• contact the subject's GP to check the medical
history (Section 11);
• keep subjects overnight when necessary; and
• review all the relevant scientific and medical
literature before starting a clinical trial.
At one time, almost all IMPs were new chemical
entities (NCEs). Now, many are biological in nature
(Section 16). Many biological IMPs - such as
proteins, 42 cytokines 43 and monoclonal
antibodies 44,45 - have been tested safely in first-inman
trials in healthy subjects or in patients. However,
compared with NCE, there is a paucity of data about
their overall safety. Some reasons why biological
IMPs, especially monoclonal antibodies, should be
seen as different from NCE are:
• The effects of proteins, especially monoclonal
antibodies, may be amplified downstream from
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