Annex D
Memo to file 3 February 1995
SUBJECT SERIOUS ADVERSE REACTIONS TO BATIMASTAT
On Monday 23 January at about 9.00 am I spoke
to Dr Richard Osborne of Addenbrookes Hospital Cambridge about
his patient, a 38 year old lady with advanced ovarian cancer,
who had received British Biotech's drug batimastat in one of our
clinical trials (D02/IVB/311). This patient had developed severe
vomiting due to paralytic ileus after drug administration, which
had persisted for one week and required hospitalisation. The ascites
in this patient had reaccumulated over the week and CT scans confirmed
the diagnosis of paralytic ileus and the ascites. Our conclusion
was that the patient had suffered peritonitis due in some way
to the administration of batimastat.
The importance of this event is that this patient
was the first patient entered into this study following a meeting
between myself, Dr Peter Brown (PB, Head of Therapeutic Area and
my reportee at British Biotech) and the London Gynaecology Oncology
Group—LGOG (about 20 oncologists including Richard Osborne,
Martin Gore, Peter Harper and David Miles) on 10 January at Guy's
Hospital. The purpose of the meeting was to discuss the high incidence
of abdominal problems including severe pain, vomiting and paralytic
ileus observed in the first few patients in study 311. At that
time seven out of nine patients treated with batimastat had experienced
severe symptoms which could be explained by peritonitis. This
was at significant variance with earlier clinical trial experience
with the drug which had shown good tolerability with two exceptions.
The most relevant one was the experience of Professor David Kerr
of Birmingham whose patients in our phase II study (309) had marked
abdominal problems compared to the other patients at other centres
in the study. The other was the use of batimastat in advanced
malignancy without ascites. At the time of the problems of David
Kerr I had asked our manufacturing and formulation department
to check that the drug supplies were within specification and
unchanged from previously. This was confirmed to me. When the
problems in 311 started to occur I asked for the same information,
which was most pertinent as the process had been scaled up and
the site of production changed. It was again confirmed that the
formulation was within specification. I was aware that we had
changed the formulation from vials to ampoules at the request
of Dr Peter Lewis (PL—my supervisor and Director of R&D)
and that while ampoules do produce small particles of glass when
broken, inhouse tests had shown that these were probably entirely
removed by a 40 micron filter.
At the meeting with the LGOG I was therefore
not able to account for why the problems were occurring, but postulated
that they may be due to the use of room temperature fluid, whereas
we had previously administered the drug at body temperature. Cool
intraperitoneal fluids are considered by surgeons to be a possible
cause for paralytic ileus although experience with peritoneal
dialysis suggests otherwise. The clinicians agreed with me that
this could explain the problem and we agreed to warm the fluids
for the next few patients. The significance of the above patient
is that she was the next patient.
It became clear to me that the formulation must
have changed in some way undetected by our specifications and
analyses. It was therefore obvious that the study should be discontinued.
I immediately went to speak to PL, just prior to his main board
meeting to inform him of the problem and the possible outcome.
He reasonably wanted some time to consider the situation. I attempted
to see him again that evening, but he had gone home after the
board meeting and saw him the next morning (24 January). Various
meetings were convened at which the following were decided:
Recruitment to the study should be halted, the
clinicians should be immediately informed and be asked to inform
their ethics committees.
The physico-chemical properties of the formulation
and previous formulations would be thoroughly investigated and
compared.
The formulation and previous formulations would
be tested in animals for potential to cause peritonitis.
I would consider how to restart the programme.
There were discussions about how and when to
tell the regulatory authorities (the MCA and the FDA). These negotiations
are not my responsibility in the organisation. My opinion, firmly
stated, was that they should be told at the same time as the clinicians.
I was surprised that this was not the unanimous view and PL, in
particular, felt we should delay apparently because of the sensitivity
with the financial markets.
I decided that while it was not in the best
interest of the company it was not my personal liability, but
did say that as I was due to meet the FDA three days later I would
be most comfortable to tell them in advance and not after the
meeting (although this appeared to be PL's favoured course). I
decided privately that I would discuss the situation with Greg
Hockel (the US regulatory affairs manager) and allow him to persuade
PL to inform the FDA immediately. With regard to the MCA, I felt
it was PL's liability (in the end a letter was sent to the MCA
on the 30 January with immediate reply). After the meeting I immediately
produced a letter for the investigators and spoke to Drs Osborne,
Smyth, Carmichael and Poole. I could not contact Drs Beattie and
Gore. Following this I heard that PL had spoken to the US and
Greg Hockel had persuaded him of the sense of informing the FDA
immediately.
On the 25th I boarded a plane for the US with
PB having first checked that the office was in order and returned
on the 28th. The meeting with the FDA was successful and we discussed
the adverse reactions briefly.
On the 30 January I went up to see PL and as
he was on the phone was invited in by Keith McCullagh (KM) our
chief executive. This was about 10.30 a.m. PL joined us shortly.
They congratulated me briefly on the meeting with the FDA and
then we talked about the issue.
KM, supported by PL, put forward the theory
that our new scaled up manufacturing process was producing a formulation
of such high quality that it was dissolving much more rapidly
than the old and the high concentrations were producing chemical
peritonitis. The fix for the problem was to halve the dose and
restart the studies. There is no data to support the theory of
enhanced dissolution, anyway batimastat appears relatively non-irritant
as a chemical, but particles in the peritoneal cavity are known
to cause physical peritonitis. KM said we would not find a difference
in the formulation and we would not be able to fix it. I should
proceed on this assumption. The meeting became slightly heated,
KM used the word "negative" and reminded me of my responsibility
to find a way of "quickly" reestablishing the clinical
trials. We talked about pleural effusion studies and PL and KM
reminded me that an inflammatory effect may be an advantage so
could we move ahead with those studies. I agreed "possibly,
but it is also possible that any defect in the formulation may
be detrimental to efficacy and tolerability." I think the
word "negative" was used again. The meeting was interrupted
by the arrival of some guest of PL.
During the day, I was told that no differences
in the formulation existed, although no-one had apparently looked
at the particles down a microscope and was also told that so far
no animals had been tested, but a meeting was due to be held that
afternoon to decide what to do.
KM came to see me after lunch. I adopted a cooperative
and pleasant attitude and told him I was not trying to be negative,
but looking for a way ahead. However I said that it appeared that
this matter was not being pursued with urgency with the specific
intent of finding a problem and fixing it and said "why had
microscopy not been undertaken and why had no animals been dosed?".
I intimated that attention should be applied there before attempting
to restart what appear to me to be very difficult studies in humans.
KM said he would see to it and he would organise a "Batimastat
Issues Team".
During the course of the next day (31 January)
I heard that a meeting had been called for 5.30 and the formulations
had been microscoped and there was no difference. It also became
clear to me that Russ Smith (RS) who is in charge of formulation
and QC and is an intelligent, able, decisive and pragmatic manager,
but has no real experience in formulation may not have the breadth
of experience necessary to judge whether bulk manufacture, milling,
wetting, mixing or autoclave cycles may be able to materially
alter the characteristics of an intra-peritoneal injectable suspension
(this is the first such product to be taken into human clinical
trials and therefore is extremely demanding).
At the meeting, RS produced 6 micrographs of
an old well tolerated formulation and the new problematic one.
It was immediately clear to me that the new formulation contained
10-20 rounded, bumpy particles of about 6 micron diameter per
field plus a small amount of rod shaped 6 x 1 micron particles.
The old formulation only contained the rod shaped particles. Not
everyone agreed with me. KM and PL had not yet entered the room.
When they did we handed them the 12 micrographs and invited them
to sort them into two lots based on the presence of rounded particles,
which they did. Checking the backs of the micrographs for the
code of the batch showed that they were 100 per cent correct.
The meeting was broad ranging in discussion.
Within an hour of this KM asked me to assume that we would not
be able to "fix" the problem, yet we had made no further
investigations. He insisted that halving the dose would remove
toxicity without impairing efficacy. This is a bold assumption.
He insisted that we would probably not be able to show a difference
between the formulations in animals. As matters became heated,
he said he wanted the study restarted with the dose halved and
I should be in agreement with this line of action "by Friday".
I responded, rather obstinately, that he should know that I would
not be able to agree to that by Friday. He said "I'm going
home". The time was 7.45.
I realised after the meeting that PL had said
very little about the advisability of restarting an ascites study.
I went to see PL on Thursday morning in his
office and met with him at about 12 noon. We had a good tempered,
soft voiced discussion. We discussed various issues and it became
clear that PL realised we needed more time before making any decisions.
He told me that KM was extremely angry and wished to fire me,
but felt that he could not because either it would cost him a
lot of money or that I would phone the Medicines Control Agency.
He apparently did not think that he needed to "put up with
being spoken back to" and wished to replace me with someone
more "pliable". He probably would not therefore meet
with me on Friday as indicated by his threat. I reverted the discussion
to the way forward with the technical issues and felt that PL
agreed with most of my reservations regarding the difficulty of
any clinical trials at present. PL also felt it necessary to speak
to me on the subject of my body language, facial expressions and
style of conversation, which is apparently angry and inflammatory.
In view of PL's reports of KM's thoughts, I thought I should commit
my current memories to paper.
3 February 1995
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