Memorandum by The Association for Human
Pharmacology in the Pharmaceutical Industry (PI 107)
1. AHPPI
The Association for Human Pharmacology in the
Pharmaceutical Industry (AHPPI) was founded in 1988. We have 152
members—physicians, nurses, clinical scientists, project
managers and various types of support staff—who work for
organisations, such as pharmaceutical companies and contract research
organisations (CRO), involved in the early development of new
medicines. Most of the big pharmaceutical companies and CRO in
the UK are represented among the membership.
The purpose of the AHPPI is to provide a forum
for continuing education in clinical pharmacology—the discipline
that underpins early development of new medicines—and in
the regulatory aspects of the early development of new medicines.
We hold symposia with invited speakers, twice yearly. Membership
of the AHPPI is £15 per year and attendance at symposia is
free.
We have links with other organisations involved
in developing new medicines, such as the ABPI, Institute of Clinical
Research, and Contract Clinical Research Association. Also, we
share some of our symposia with the Clinical Section of the British
Pharmacological Society, an organisation whose members are mostly
from university departments of clinical pharmacology. The AHPPI
is run by a committee and provides information to members via
a website (www.ahppi.org.uk).
2. PHASES OF
DEVELOPMENT OF
A NEW
MEDICINE
Medicines research is traditionally separated
into four phases, although in practice they often overlap. Phases
1 to 3 are done before a licence to market the new medicine is
applied for, and phase 4 is done after a licence has been granted.
During phases 1 to 3, the material being tested is called an investigational
medicinal product (IMP), whereas after licensing it becomes a
medicinal product or simply a medicine. Phases 1 to 3 of a successful
IMP can take up to 10 years. Few IMP survive all of the phases.
The failure rate is highest in phase 1. The phases of development
of a "typical" new medicine in humans are shown below.
|
| Phase | Number and type of subject
| Questions asked |
|
| 1. | 100-200
healthy subjects
| —Is the IMP safe in humans?
—What does the body do to the IMP? (pharmacokinetics)
—What does the IMP do to the body? (pharmacodynamics)
—Might the IMP work in patients?
|
| 2. | 200-500
patients with the target disease
| —Is the IMP safe in patients?
—Does the IMP seem to work in patients? (efficacy)
|
| 3. | 1,500-5,000
patients with the target disease
| —Is the IMP really safe in patients?
—Does the IMP really work in patients?
|
| 4. | many thousands
patients with the target disease
| —Just how safe is the new medicine? (pharmacovigilance)
—How does the new medicine compare with similar medicines?
|
|
Trials of IMP in healthy subjects were excluded from the
Medicines Act 1968, simply because healthy subjects derive no
therapeutic benefit from an IMP. However, all clinical trials,
including ones in healthy subjects, have been regulated since
the EU Clinical Trials Directive 2001/20/EC was implemented in
the UK on 1 May 2004. The main impact of the Directive is on phase
1 trials in healthy subjects.
3. PHASE 1 TRIALS
IN HEALTHY
SUBJECTS
IMP must not be tested in humans before the necessary pre-clinical
studies—the chemistry, pharmacology, toxicology and pharmacy
of the IMP—have been completed.
Most IMP can and should be tested first in healthy subjects.
But the risk must be minimal. The first trials of an IMP in healthy
subjects are usually of single doses of the IMP of increasing
size. The next trials are usually trials of repeated doses. The
aims of the early trials in healthy subjects are to assess the
tolerability, safety, pharmacokinetics, and pharmacodynamic effects
of the IMP, and to compare the findings with those in animals.
Subsequent trials in healthy subjects may:
— assess the efficacy of an IMP or to define the
dose for trials in patients, by measuring biomarkers or using
challenge agents against which the IMP is tested;
— compare the bioavailability (how much gets into
the bloodstream) or the bioequivalence (if the amount that gets
into the bloodstream is not significantly different) of different
formulations of an IMP;
— assess the effects of things such as food, gender,
age and genetic differences on the activity of an IMP;
— assess the possible interaction of an IMP with
marketed medicines; and
— assess the absorption, breakdown and elimination
of a radiolabelled IMP.
Some of these trials, such as interaction trials, may be
done during any phase of IMP development. Compared 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. Trials of IMP in healthy subjects have
a good safety record.
4. UK PHASE 1 TRIALS
The AHPPI surveyed 29 UK phase 1 units that did trials of
IMP for the pharmaceutical industry during 1999 and 2000. The
total number of trials per year was just over 600. 82% were done
by CRO, 17% by pharmaceutical companies with their own phase 1
units, and 1% by academic departments that provide a service to
the pharmaceutical industry. Ethics committees took an average
of 14 (range 7 to 28) days from submission of an application to
written approval. That response time formed the basis of the target
of an average of 14 (maximum 21) days that the MHRA set itself
to review an application for a phase 1 trial, after implementation
of Directive 2001/20/EC.
Since the AHPPI survey, the academic departments have stopped
their service and two of the pharmaceutical companies have closed
their phase 1 units. So, probably 90% of commercial phase 1 trials
in the UK are now done by CRO. Some of the CRO are based in or
are close to NHS hospitals, for safety reasons.
One of the CRO (HMR) surveyed over 300 phase 1 trials that
it carried out from 1993 to 2001. About one third of the trials
came from UK sponsors, one third from sponsors in other European
countries, and one third from countries outside Europe, mainly
Japan and the USA. The average income per study in 2002 was £284,000
(range £40,000 to £830,000). If we assume that the data
for HMR apply to the 600 phase 1 trials done in the UK each year,
the total income is about £170 million per year, two thirds
of which are exports. If companies do their phase 1 trials in
the UK, they are more likely to do their late phase trials in
the UK ("pull-through trials") as well. Also, phase
1 units use various subcontractors and support services, which
need to be taken into account when assessing the overall contribution
of phase 1 trials to the UK economy. Although income from phase
1 trials is small in comparison with that from the pharmaceutical
industry as a whole, phase 1 trials are a vital part of medicines
development.
5. COMPARISON OF
EARLY AND
LATE PHASE
TRIALS
Clinical development of a new medicine can take 10 years
and cost up to £500 million, so time is money. At one time,
only academic clinical pharmacology units did phase 1 trials in
healthy subjects in the UK. In recent years, CRO have taken over
that role because they can provide an efficient, effective and
high-quality service that enables companies to plan and execute
the early clinical development of their IMP to tight timelines.
The ABPI estimates that the UK does over half of the commercial
phase 1 trials done in Europe.
The pharmaceutical industry would like but rarely gets such
a service for phase 2 and 3 trials in the UK, which are usually
done in a hospital setting. Recruitment of patients is often slow.
Failure to keep to the protocol can render data unusable. Also,
failure to comply with good clinical practice may impair the quality
of the data, even if usable. Payments demanded by investigators
vary widely for the same trial, and can be excessive. Academic
institutions add overheads, often high, to investigators' charges.
A strong pound sterling makes matters worse for overseas' companies.
For those reasons, companies are increasingly placing their phase
2 and 3 trials outside the UK, in low cost areas such as Eastern
Europe, Russia and India.
6. IMPACT OF
DIRECTIVE 2001/20/EC ON
UK PHASE 1 TRIALS
Feedback from AHPPI members since implementation of the Directive
on 1 May 2004 indicates that the MHRA has been keeping to its
target of 14 to 21 days to review applications for phase 1 trials,
whereas the time for ethics committees to review applications
for phase 1 trials has increased. Also, the MHRA and ethics committees
are both proving slow to review and approve substantial protocol
amendments, which are often essential to during phase 1 trials.
That is causing serious difficulties for many CRO. Also, there
is uncertainty about the future of many of the ethics committees
that are currently allowed to review phase 1 trials in healthy
subjects.
The evidence so far suggests that the Directive has reduced
the number of phase 1 trials being done in the UK. Some pharmaceutical
companies are choosing to do their phase 1 trials in EU countries
that have not yet fully implemented the Directive. Pharmaceutical
companies from countries, such as the USA and Japan, that are
outside the EU are deterred by the extra bureaucracy involved
in doing their trials in the EU, and not just the UK.
We intend to repeat our AHPPI survey of UK phase 1 units
one year after implementation of the Directive, to get more objective
information about its impact.
7. REFERENCES
Calder N, Boyce M, Posner J, Sciberras D. UK phase I units:
an AHPPI survey 1999-2000. Br J Clin Pharmacol 2003; 56: 76-79.
Boyce M, Warrington S. 312 studies of IMP in healthy subjects.
Int J Pharmaceut Med 2002; 16: 179-183.
November 2004
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