Examination of Witness (Questions 480
- 498)
TUESDAY 28 JULY 1998
DR PETER
LEWIS
480. In terms of the results, were the results
hopeful?
(Dr Lewis) Yes, they were very positive.
481. Because Dr Millar says that the results
from Study 214 appeared to be in favour of Zacutex but were not
statistically significant. How can you have results that are not
statistically significant?
(Dr Lewis) They were statistically significant as
far as deaths were concerned but they were not statistically significant
as far as improvement in organ dysfunction. It was a sort of box-ticking
exercise. Not all the efficacy parameters that were in the protocol
were positive but the majority of them were. In particular, if
we just looked at the patients who were treated within 48 hours
then they were highly statistically significant. It was a mixture.
482. In what way did the subsequent trials differ,
the American trials from the European?
(Dr Lewis) They were almost exactly the same and purposely
so because we had got a positive result, except that we elected
to put in a lower dose in addition to the one that had worked
in Europe. That was as a result of discussions that we had with
FDA.
Chairman
483. It was two trials in one?
(Dr Lewis) Three: placebo, low, high dose.
Dr Jones
484. Do you think the results coming through
on the second trial would justify unblinding the study?
(Dr Lewis) No, I do not. There was not any justification
for unblinding it. As I said in my letter to the Chairman, which
I think you have got, there was a complication about the results
in that American study in that the protocol was quite complicated
and there was a provision in it that half way through the study,
or when a certain number of patients had been accrued, there was
a statistical committee that was supposed to convene to determine
what the actual number of patients should be in order to get a
statistical result. So that statistical committee, which met at
the beginning of May, had to be provided with data on the study
and there were elaborate precautions so that statistical committee
got these data in a blinded form so that the study would not be
compromised.
Dr Gibson
485. They changed the end point too, did they
not?
(Dr Lewis) They did?
486. It was death, mortality.
(Dr Lewis) No, I think that was done at an earlier
stage.
487. I am just reading the shareholders' report,
and I always believe what it says in shareholders' reports. It
says there: "The change in the number of patients in 215
to 1,500 changed the end point to all cause mortality." This
was issued after the meeting on 9 July 1997.
(Dr Lewis) I accept that. It was a study where there
was a lot of to-ing and fro-ing with FDA about what the actual
end point would be. The idea was that the FDA wanted death as
the end point and we tried to argue, because it would mean fewer
patients, that improvement in organ function should be an end
point.
Dr Jones
488. How important was it for the company that
Zacutex should come to market?
(Dr Lewis) It was what all this recruitment of commercial
people was about. It was important from that point of view. From
the long-term point of view Marimastat and the matrix metalloproteinase
programmes were much more important.
Chairman
489. Just two quick questions if I may, Dr Lewis,
on clinical trials. I think you have told us the extent to which
unblinding of clinical trials proves those trials invalid. You
have told us that in most cases it would do. Only if there was
some overriding on something as serious as cancer with a high
mortality rate would the FDA possibly consider allowing an unblinded
trial to still have some validity.
(Dr Lewis) Correct.
490. But, even so, if you had known Dr Millar's
allegedly repeated unblinding of trials and you were still his
superior, his boss, what action would you have taken?
(Dr Lewis) I would have taken it very seriously because
it really compromised what we were trying to do. It is difficult
to say in hindsight but I would certainly have discussed it with
Dr McCullagh as to what we should do about it. I think we would
have disciplined him in some way, possibly even fired him as a
result of doing that.
491. Because it is considered to be a very serious
offence within your profession and your industry?
(Dr Lewis) Yes. You could consult anybody but it is
just a no-no, one must not do it.
Mr Beard
492. The broad drift of the story that has been
revealed in these hearings is one where there was a tension between
the business run side of the organisation which needed to present
a confidence inspiring case to the outside world, and you and
your colleagues on the research and development side who were
faced with the normal features of things going right and things
going wrong but you feared if you told them the story of things
that went wrong it would affect the image on the outside world.
There was a constant tension between these two that erupted, it
seems, into this sort of picture that we have been hearing about.
Is that tension not inherent in this type of structure of a company
which is valued entirely on the expectations and the results of
clinical trials and research?
(Dr Lewis) Yes.
493. In the results of British Biotech's history,
is that not likely to have some implications for the rest of the
biotechnology industry?
(Dr Lewis) I think it happens all the time. If you
look in the US, and our other 32 other biotech-type companies,
it happens all the time. When unfortunate results occur confidence
drops and there is a big problem, the share prices plummet. That
is important simply because it is very, very difficult to raise
more money to carry on with the research. There is this constant
tension. However, we did give out bad news. We had four compounds
that went wrong and we told the market about that and the analysts
accepted that and we went through the explanation as to why it
was and why this next one was likely to be better and so on and
so forth. These sorts of problems that happen in biotech companies
happen all the time in large pharma companies as well.
494. But there is a lot more substance to withstand
the shock.
(Dr Lewis) That is right. There is a famous phrase
in biotech that Jurgen Drews, the Head of Research at Roche, said
"biotech will never become mature until they learn to bury
their dead at night".
495. Is it just burying the dead at night or
is it that these companies that are not Roche or Zeneca or Glaxo
or any of these big companies are entirely dependent on expectations
which they are then under huge pressure to deliver, although the
odds are somewhat against delivering them in many cases? I am
trying to draw out from this what are the general lessons to be
learned from the story we have been hearing. It makes one wonder
whether the structure of biotechnology companies is suitable for
a stable development of this type of technology.
(Dr Lewis) I think the problem comes when biotechnology
companies venture too far into the clinical evaluation of compounds.
It is fine when biotech companies are largely working at the bench,
developing new and innovative technologies and approaches and
then they do the licensing deals with the large companies which
pick and choose the new technology that they want. Where you run
into difficulties is when you have a situation where the politics
of the company or the strategy of the company is that they want
to do everything themselves, including commercialisation. I think
commercialisation is almost always a wrong thing to do for a company
that has just started. As far as late stage clinical trials are
concerned, you could also say that is not a very good thing for
a very small organisation to do because you need a huge amount
of money. That is why the company had to raise such a large amount.
Phase three trials are very, very expensive. The answer to your
question is the biotech company is better at the earlier stage
of research and the early evaluation of the compounds, the problem
is the market does not value those companies anything like so
highly. There is a Catch 22 there.
496. What would you do about that? From your
own experience, having lived through this, what would you do about
reconciling the pharmaceutical regulations for clinical development
and the Stock Exchange rules?
(Dr Lewis) I think the regulation has got to be the
same for everybody, whether you are small or big, that is a given.
As far as the regulation of the companies is concerned, I think
one of the problems with British Biotech was really amongst the
non-executives there were not enough people, indeed any people,
who had real experience in the area of medical and clinical research.
When I went to the company originally before we floated on the
Stock Market we had two very experienced ex R&D Directors
on the board, Sir David Jack from Glaxo and we had Sir Charles
Reece, ex-ICI. They were people that I, as the R&D Director,
could go on and talk to and I frequently did. As the company became
a bit more of a conventional sort of Stock Market company, then
we got non-executives on to the Board who are generalists, they
are businessmen, so the things that they helped the company with
and what was talked about at the Board meetings were more things
like VAT around Europe or delivery systems or warehousing, things
which were absolutely miles down the track and it moved further
and further away from the reality of the matter which was what
was going on with the R&D, so I think, as far as what should
be done, I think these companies ought to have in a mandatory
sort of way medical and technical people with experience of the
industry in the non-executive positions.
Dr Kumar
497. Dr Lewis, given the experience of the British
Biotech saga which we have been discussing, what impact do you
think this is having on the biotechnology industry as a whole?
(Dr Lewis) Well, it is obviously not helping. I think
it has given a bad image of our industry. It may be a sort of
maturation process. I think it ought to scare off the sort of
individual investor, as it were, in biotech. I think the institutions
who have 1 or 2 per cent possibly of their funds in high-tech,
very high-risk companies, they are aware of what these risks are,
but I think it has probably shocked a lot of people who have been
individual investors in the sector. We do not have a lot of them
in Europe anyway and that is a sort of American phenomenon, but
I think that if you are looking for general issues, I think the
way that investors look at these type of companies, they are probably
going to look more realistically at companies that are doing their
own clinical research and their own commercialisation strategies
and, as I just said, I think that they will then realise as the
sector matures that the place of biotech is as a sort of resource
for larger companies and in fact the value of biotech is got out
of deals with larger concerns, and that is probably the best way
of financing the industry.
498. Do you think it will take a little longer
to get the confidence in the biotechnology industry as a whole?
(Dr Lewis) Yes. I do not know how long it will take.
One must not think that British Biotech is a great exception in
all of this. There are huge variations in valuation in these companies
and, as a result of this, I have been looking at some statistics
about it. In the United States with 331 companies, et cetera,
there are just as wide variations in what happens to those companies
and similar sorts of events which push the stock price up or down.
We saw a huge rise in stock prices of a biotech company in the
States when the results came out about treating mice with cancer
with Endostatin, for example. That is bound to happen, I think,
because these companies want to boast about their achievements
even if they are at a very early stage, but it is not exceptional.
What is very exceptional about this case is the fact that basically
there is a whistle-blower where Dr Millar has been making allegations
of wrongdoing as opposed to bad luck in the company, and that
is very unusual. I cannot think of another example of a so-called
whistle-blower in biotech or pharma at all. The last one I can
remember was at Roche in 1960 odd. It is just very unfortunate
and I think that if that is what has made this whole thing so
painful, the facts of what happened when you actually analyse
them are not, I think, in any way horrifying or whatever, but
it is unfortunate because what has happened to the company is
that they failed to get a product approved.
Chairman: Dr Lewis, you have actually summed
up in the last few words the reason why this Committee is having
this inquiry. We are trying to find out what is unusual about
this particular company, why this particular company despite all
its best endeavours to do good ethical work for sick patients
has come into the limelight, why its share price has dropped and
why it has become a controversial company. You have summed up
the reason in your last few words, because someone decided to
go outside the normal confines of a company boardroom and say
things outside that perhaps normally would have been discussed
inside. We shall produce our report in due course. It is thanks
to you and others that we shall be able to do so. May I thank
you for the evidence you sent us in writing, for coming along
this afternoon and by yourself sustaining very considerable questioning
for nearly an hour and a half, we are very grateful to you. I
would like you to go away bearing in mind that this Committee,
and I imagine the majority of Members in this House, wish to see
companies such as British Biotech, and other companies for which
you have worked and will work, succeed because we know at the
core of it all is a group of dedicated men and women seeking to
find treatments for patients with terrible diseases. We wish everyone
working in this field well but we do not wish to see any conflict
between financial investment and medical ethics. That is what
we are trying to get to the root of. Thank you very much.
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