APPENDIX
BACKGROUND INFORMATION
Outline summaries of the clinical development
process and the centralised procedure are set out below to assist
with the understanding of this circular. The detailed processes
and requirements are not described.
1. CLINICAL DEVELOPMENT
Description of clinical trials
Once a potential new drug is identified pre-clinical
research is carried out to explore the drug's efficacy and safety
prior to administering it to humans. The objective of clinical
trials is then to determine whether when the drug is administered
to humans it is effective, safe and of suitable quality to be
licensed by regulatory authorities. Traditionally the clinical
development of a potential product is divided into three phases.
Although the precise description of these phases varies from country
to country, British Biotech has in general attempted to maintain
the definitions that it set out and explained in its Report and
Accounts for the year ended 30th April 1993. These descriptions
were broadly as follows:
ICH E8
3.1.3
(a) Phase I
ICH E8
3.1.3.1
Phase I clinical trials are the first studies
of a drug in man or so called "healthy volunteers".
They are designed to test the safety of a potential drug and its
handling in the body. In these studies, up to 100 healthy human
volunteers may be given the drug. British Biotech often undertakes
multiple Phase I studies so that the characteristics of a new
drug in human volunteers are as complete as possible.
ICH E8
3.1.3.2
(b) Phase II
If Phase I is successful, the drug will enter
pilot efficacy trials in patients, which are known as Phase II.
At this stage, the drug may be evaluated as a treatment for one
or several clinical conditions and the optimum dosage and frequency
of administration will be established. A series of Phase II studies
may be undertaken involving between 50 and 300 patients for each
indication.
ICH E8
3.1.3.3
(c) Phase III
For a new drug to be approved for marketing
it must undergo trials in the target patient population of sufficient
scale to demonstrate statistically significant benefit and long
term safety. During these Phase III trials, typically involving
a few hundred to several thousand patients dependent on the indication,
the drug's effectiveness is compared with placebo and often with
recognised treatments under conditions reflecting normal clinical
practice.
ICH E8
3.1.3.1
In the USA the FDA refer to trials that are
suitable to support an application for a New Drug Application
("NDA") as "pivotal" trials. These are normally
Phase III trials but could also be a Phase II study as long as
the study is randomised and controlled. The designation of a study
as "pivotal" is usually agreed with the FDA before a
study starts. The oncology division of the FDA has at times used
different designations for clinical trials with cytotoxic drugs
as they cannot be given to healthy volunteers. The first trial
in patients is referred to as Phase I, by the oncology division
of the FDA, and to differentiate the various stages of clinical
trials reference is at times made to Phase I(b) and Phase I/II.
While British Biotech tries to maintain simplicity, at times in
the US it is forced to adopt local nomenclature.
ICH E8
3.1.3.4
Following the regulatory approval of a drug,
it may be necessary to conduct further clinical trials which are
referred to as Phase IV trials.
ICH E6
6.4
Clinical trial protocol
Before commencing any clinical trial it is necessary
to agree a protocol setting out in precise terms the purpose of
the clinical trial and the precise manner in which it is to be
conducted.
ICH E6
6.4.1
The objective, or "end point", which
is investigated by the trial has to be defined precisely and prospectively.
In general, protocols have to be approved by the regulatory authorities
prior to the start of the trial. This ensures that if the trial
should prove positive in the manner in which it is designed it
will be sufficient to support an application for a product licence.
It is for this purpose that meetings are normally held with regulatory
authorities during the clinical development programme.
ICH E8
3.2.2
It is important that the terms of a protocol
are, so far as possible, not altered once the trial has started
otherwise the integrity of the trial result can be compromised.
It may, however, for safety or other unforeseen reasons be necessary
to alter the protocol; this can be done with the approval of the
Company, the investigators, the relevant regulatory authorities
and ethical review boards.
ICH E6
Every clinical trial intended to be used in
support of an application for registration should be conducted
in accordance with standards of good clinical practice. These
standards are in the process of being harmonised across Europe,
the USA and Japan and an internationally recognised set of rules
of Good Clinical Practice ("GCP") have been proposed
by the International Conference on Harmonisation. Pending the
implementation of GCP, locally applicable regulations must be
observed. These vary slightly from country to country but are
broadly similar.
ICH E9
2.3
2.3.1
2.3.2ICH E8
3.2.2.5
To be accepted as the basis of regulatory approval
clinical trials must normally be controlled, randomised and double-blind.
Controlled trials are ones in which the potential new drug is
compared either to a placebo or another drug currently approved
for the condition. Randomisation is the process by which patients
entering the trial are randomly allocated to either the group
receiving the drug that is being tested or to the group receiving
the placebo or comparator drug. The purpose of the double-blind
is to ensure that neither the patient nor anyone else involved
in the conduct of the study is aware which of the drug or the
placebo or comparator the patient is receiving. It is difficult
to double-blind some clinical trials as there may be differences
between the method of administration of the potential new drug
(for example orally) and the existing treatment (for example intravenously)
against which is is being tested.
Data analysis and integrity
In order to ensure that the data from clinical
trials is as accurate as possible, Clinical Research Associates
are employed throughout the conduct of a study to check and verify
the data entered in the patients' case report forms.
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2.3.1
Double-blind conditions should be maintained
while the study progresses to ensure that neither the patient
nor anyone else involved in the conduct of the study is influenced
in any way by knowledge of which treatment the patient is being
given. The maintenance of the blind and hence the integrity of
the data is therefore vital in order to persuade regulatory authorities
of the validity of trial results. The blind is not lifted normally
until after the last patient in the trial has finished all his
or her necessary follow-up procedures as laid down in the protocol
and his or her patient case record form has been entered into
the study database. Only at this stage can the results of a clinical
trial be discovered by analysing the data in light of knowledge
of the treatments that the patients have received.
ICH E9
2.3.1
4.1
4.3
Unblinding of a trial prior to the end-point
defined in the trial protocol should only take place in two circumstances:
first, where an interim analysis of the data is provided for in
the protocol previously agreed with the regulatory authorities;
secondly, when there is an acute concern with regard to a safety
aspect of a trial. In the latter case it is necessary to inform
the regulatory authorities. Unplanned interim analysis to provide
a look at drug effect should not take place. If done, the integrity
of the study is jeopardised and a statistical penalty may be imposed
on the data produced by the trial.
ICH E9
2.3.1
It is also possible for an individual patient
to be unblinded should the clinical investigator deem it appropriate
for safety reasons. This is usually done only after consulting
the Company and should be properly documented in the study files.
In order, therefore, to obtain the maximum information
from a clinical trial it is necessary to complete the study according
to the protocol and to ensure that the data are kept strictly
blinded.
Any inclination to unblind at the data part
way through a trial must be resisted at all costs. It is contrary
to GCP. It may invalidate the study data and ultimately delay
getting a drug registered.
Marimastat clinical trial programme
Marimastat works in a wholly different manner
from cytotoxic, anti-cancer drugs and, therefore, the clinical
trial programme had to be designed in a different manner. The
two main differences are first that marimastat, as it is not highly
toxic, could ethically be given to healthy volunteers. As a result,
a standard Phase I clinical trial programme in healthy volunteers
could be conducted during which the safety of the drug and the
manner in which the body dealt with the drug (pharmacokinetics)
could be
Supplementary Memorandum submitted by
British Biotech plc Letter to the Clerk of the Committee from
Dr Keith McCullagh, Chief Executive Officer, British Biotech plc
I recognise the wish of the Committee to understand
more fully the events which led up to Dr Millar's public allegations
against British Biotech. Following the evidence given to the Committee
on 15 July 1998[13]
by Ms Jane Henderson, we thought it might be helpful to provide
the Committee with information on at least some of the contact
between Ms Henderson and Dr Millar and its timing, prior to Ms
Henderson's visit to the Company on 12 February 1998.
All telephone calls made from British Biotech
are automatically logged. I attach the log (Annex 1) of all calls
registered on the direct telephone of Dr Millar for the first
quarter of the current year, up to and including the day of Dr
Millar's suspension, 11 March 1998.
The telephone number 0171 774 1134 is the direct
line of Ms Henderson at Goldman Sachs. Telephone calls from Dr
Millar's direct line to this number were logged as follows:
Date
| Duration of call
|
5 February 1998
| 35 seconds
|
5 February 1998
| 34 seconds
|
5 February 1998
| 19 minutes 37 seconds
|
6 February 1998
| 26 minutes
|
11 February 1998
| 13 minutes 28 seconds
|
13 February 1998
| 32 seconds
|
13 February 1998
| 34 seconds
|
We hope this information is useful in helping the Committee
further clarify the chain of events.
22 July 1998
13
HC888-ii Back
| 
