Examination of Witnesses (Questions 80
- 99)
WEDNESDAY 1 JULY 1998
DR KEITH
MCCULLAGH
AND DR
PEDER JENSEN
80. So you stand completely by the press releases
of 1995?
(Dr McCullagh) Absolutely. They were factually correct
and they reflected our view of the development programme and its
phases and we said very clearly it would require confirmation
in phase three. Those phase three trials are now under way.
81. Dr Millar has expressed serious reservations
about the speed with which marimastat can be brought to the market.
It does strike me that you were working on a timescale of two
to three years to market this product.
(Dr Jensen) To complete the clinical trials, not to
market the compounds. When you complete clinical studies, when
I was saying that about a third of the studies will be clinically
completed next year, if these studies are positive they could
be the basis of a submission. It takes about six months to put
a submission together. That is submitted to the health authorities
and it takes about a year to get a view and outcome from that
submission. So at the very earliest, we are talking about marketing
about 18 months after the studies have read out.
82. So this is in a sense the best possible
scenario? There is another scenario, which is perhaps it will
be three years or five years?
(Dr Jensen) Exactly.
83. There is another scenario which is that
it will fail at phase three?
(Dr Jensen) That is correct.
84. Do you accept within this new industry of
biotechnology, especially when we are looking at cancer drugs
when there is a billion pound market out there, it is particularly
vulnerable to hype? Whether it is your press releases or the use
made of them by the media, there was certainly a great deal of
hype in 1995-96?
(Dr McCullagh) We have an obligation to disclose the
data from our development programmes. It is such an important
component of the company's value that it is very material to shareholders
to know what the status is. We reported that data on two occasions
in 1996 and in 1995 at our half year results presentation, and
when we are making the presentation normally we report the data,
and then again when we were making a presentation the following
May to the American Society for Clinical Oncology. We simply reported
what was being said to the clinical oncologists at that academic
meeting. We verified these press releases at the time, they are
factually correct, they contain all the information available
at that time, and indeed nobody, including the SEC, has been able
to draw our attention to any material omission or error of fact
in those statements.
85. We are aware from Dr Millar's evidence about
unblinding blind trials, and that happened on two or three occasions.
Was it not your responsibility as chief executive to admonish
Dr Millar for unblinding these blind trials? This cannot happen
commonly within drug research, surely?
(Dr McCullagh) Let me make a brief comment and then
perhaps ask Dr Jensen to talk about that in more detail. The first
time I became aware that any of our studies had been unblinded
was in May last year when Dr Millar reported to me that he had
indeed unblinded two of our studies earlier in the year because
he had safety concerns. He said those safety concerns had gone
away, there were no safety issues, he had stopped monitoring the
studies, and I did admonish him and said, "That is improper
practice, it does not follow good clinical practice guidelines,
don't do it again."
86. Well he did. A second and a third time.
(Dr McCullagh) And I have to say that I valued his
contribution to the company at that time. I believed he was a
senior executive responsible for our clinical programmes and would
conduct himself with the appropriate professional standing.
87. I am amazed this is allowed within any kind
of medical protocol.
(Dr McCullagh) It is not allowed, Dr Williams.
Dr Williams: It is not allowed, yet it happened
a second and third time.
Dr Jones
88. You are saying there are no circumstances
in which it might be permitted?
(Dr Jensen) With studies you have a trial protocol
and in that trial protocol you define what kind of patients you
want to investigate, you decide what kind of design, does it have
to be double-blind or randomised, and you also decide in this
protocol the primary end-point that needs to be investigated.
You also, based on your primary end-point, define the number of
patients you need in order to test your hypothesis. So if you
have a certain hypothesis you may need 1,500 patients to test
that hypothesis and it is unethical and the company would not
include more patients than actually would be needed to test that
hypothesis. The conduct of the trial is set in the trial protocol.
That trial protocol is then submitted to the health authorities.
In the United Kingdom it is to the MCA. In the US it is to FDA
and after a certain waiting period, in the US it is 30 days and
in the United Kingdom it is 28 days, if we do not hear anything
from the health authorities we would then start the study.
Dr Gibson
89. Is that because it goes to the Ethics Committee?
(Dr Jensen) That is the regulatory aspect. In addition
of course you speak to investigators willing to participate in
the study and after you have got commitment from them you make
a submission to the Ethical Review Board. It is not only the investigator
that is signing the contract to investigate a certain drug in
patients but they also have to submit that to the Ethical Review
Board.
Dr Jones
90. Could I just interrupt. We have not got
very much time and we have got documentation about the process.
The question I asked was were there any circumstances in which
it was appropriate to unblind? If you could briefly tell me whether
it is yes or no and perhaps when the circumstances arise.
(Dr Jensen) The only circumstances where it is allowed
is if it is included in the protocol which you can do—which
was not the case in these unblindings—or if you have an
unexpected safety issue.
Chairman
91. Dr McCullagh told us that Dr Millar had
told him that it was a safety issue. That is why he unblinded
it.
(Dr McCullagh) Yes indeed. If there was a safety issue
there are proper procedures to go through. I certainly would have
been expected to have been informed at the time. There are SOPs
in place. The regulatory authorities should be informed. The hospitals
conducting the study should be informed. None of that was done.
Those procedures were not followed.
Chairman: I wonder if I could invite Dr Jones
to go on to Zacutex because we are short of time.
Dr Jones
92. I think in a sense we have covered that.
I just wanted to go back on this. Did Dr Lewis never discuss this
issue with you in relation to the unblinding?
(Dr McCullagh) I asked Dr Lewis whether he had received
information from Dr Millar about unblinded studies and he said
absolutely not. He reported to me that he had made it absolutely
clear to Dr Millar that unblinding should not take place at any
time.
93. In relation to the press releases at that
time they were more optimistic than the time-scale that Dr Jensen
is telling us about now, 2001. Were you not anticipating that
you would have the drug to market in a couple of years?
(Dr McCullagh) No, we said in 1997 that the first
study of marimastat the definitive phase three trial, would take
approximately two years to complete. We started in summer 1996
and it is now summer 1998 and we expected it to take approximately
two years and it will be complete by the end of this year and
will allow us to report the data in the first quarter of next
year. That is entirely consistent with the plan we set out in
1996. We have, however, during those two years started a rolling
programme of ten further studies including two sets of studies
in combination with cytotoxics and another two studies being conducted
by oncology academic groups where we supply the drugs and they
manage the study. Those studies will all report over that three
year time-scale. Of course we will submit for registration, as
Dr Jensen has said, as soon as we have the data on efficacy and
safety that allows us to make a submission.
94. When you sent Dr Millar to the United States
to see the Securities and Exchange Commission did you discuss
with him what you were going to tell them in relation to that
inquiry?
(Dr McCullagh) No. The Securities and Exchange Commission
were enquiring into some technical issues relating to the FDA's
approach to testing cancer drugs. We think the SEC had a misunderstanding.
That subsequently proved to be the case. Our lawyers say that
there is no basis for any suggestion that the company has violated
US securities law. In fact, six or seven of our executives have
given information to the Securities and Exchange Commission and
their testimony has been uniform and consistent and I do not believe
that the SEC has ever found any cause.
Dr Turner
95. Going back to your phase two trials you
are very emphatic about the apparent effect on tumour antigens
in circulation but can you tell us a little more about the actual
effects on tumours themselves in that trial? As I remember from
reading these papers one of the things that Dr Millar appeared
to discover having unblinded the trials was that there was a very
big question mark about effectiveness.
(Dr McCullagh) There is only one marimastat study
that was unblinded improperly by Dr Millar and that is the first
one in pancreatic cancer which is a comparison of three different
doses of the drug against a control drug, a chemotherapy agent
called Gemzar. He has indicated he thought the results when he
looked at them were disappointing but he has not, as far as I
know—you may ask him I am sure—said that they are
consistent with the drug not working. He is simply saying it may
not work better than Gemzar. We do not know the answer to that.
The study is still on-going. It will not finish until towards
the end of this year when we will have the data. It is impossible
to draw meaningful conclusions half way through a clinical trial
which has a protocol of defined patient numbers until you have
completed the trial according to the protocol and done the statistical
analysis.
96. You have not answered my point as to whether
the effect on tumour antigens was matched by an effect on the
tumours themselves.
(Dr Jensen) We are finding that out of course in the
phase three trial but in the phase two trial—
97. I am talking about the phase two trial.
(Dr McCullagh) I understand what you are saying. In
the phase two trial, patients who received the drug only did so
for 28 days which was a pretty short period to assess the effect
on the tumour. However, for patients who were also allowed to
continue on to a compassionate use of protocol, if they wished
to and their doctor wished to, I can tell you that those who did
continue on drug lived twice as long as those who did not. Those
who had a good response in terms of tumour antigens lived approximately
twice as long as those who had poor results. So the results on
cancer patient survival from those phase two trials is consistent
with the drug having a dramatically beneficial effect but of course
those are not randomised defined studies. That is what we are
doing now in phase three. We hope to be able to confirm that data
from the phase three trials.
(Dr Jensen) The short answer to your question is 28
days is not enough to assess clinical efficacy in phase two and
that was the time we were allowed to treat the patients.
Dr Gibson
98. A quick answer to this one please. Twice
as long. How long is twice as long for patients surviving, one
month or one week?
(Dr McCullagh) Because it is a spectrum some patients
survive one month, some survive one year. You are talking about
two curves. One is a steep curve and one is a shallow curve.
99. In this cycle it is a five year cycle for
success.
(Dr McCullagh) If you take median survival it is six
months to twelve months.
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