Annex D
Memo to file (15/2/95)
SUBJECT ADVERSE EVENTS ON BATIMASTAT
A "Batimastat issues meeting" was
called on 10 February. Mike Wood, Russ Smith, Alan Davidson, Alan
Drummond, Peter Brown and Peter Lewis were present. PL called
the meeting and said he would issue a report, but no report has
yet been forthcoming.
The meeting focussed on recent findings relating
to batimastat.
Alan Davidson reported that no differences in
the bulk material had been detected except for the slight toluene
content following recrystallisation. There was the possibility
that with this highly insoluble compound that different states
with different dissolution characteristics dependent on Van Der
Walle forces could exist, this could be detected by dissolution
testing.
Russ Smith reported that he had not found any
analysable differences between this formulation and others although
he said that X-ray crystallography was unable to completely exclude
the possibility of different polymorphs. He presented EM pictures
to show that both formulations were the same, I pointed out that
the homogeneity was different from the clear heterogeneity of
particles within formulations and the apparent differences between
formulations seen on light microscopy and was there a preparation
artefact? RS thought there was not. There was no satisfactory
explanation for the apparent differences on light microscopy.
The EM pictures of the bulk compound appeared possibly different
in terms of aggregation although the size and shape of the individual
crystals or particles seemed the same.
Al Drummond reported that in vivo culture of
human umbilical epithelial cells had not shown any signs of toxicity
with concentrated new and old formulations, arguing against a
direct chemical effect.
Mike Wood reported that he had found no particular
inflammatory effect of the two different formulations other than
an equal mild dose related effect in three rodent species. He
had found a very mild effect (grade II out of V) with toluene
in dextrose. He had found an apparent increase (4) in blood
levels with the new formulation compared with the old. (This was
repeated the next week and found to be consistent). This confirmed
that there was a biological difference between the formulations
without confirming an inflammatory effect.
I reported that a patient from the Churchill
hospital had developed peritonitis, paralytic ileus and had died
at the start of the week. At post mortem cause of death was reported
as "chemical peritonitis" (the pathologist would not
have been able to distinguish between physical and chemical causes).
PB and I also reported that we had now received adverse reports
from France and based on these recent reports had stopped all
intra-peritoneal studies. We reported the change of batch at Oxford
in the intra-pleural study which had apparently caused a reduction
in tolerability. We also reported that while the current formulation
was clearly different from previous formulations, the picture
was not absolutely clear cut and the formulation used at Birmingham
by Professor Kerr in the phase II study had, in his opinion been
causing chemical peritonitis, but at the time that I reviewed
the situation with him we concluded that his experience was atypical
and the experience of the other centres indicated that chemical
peritonitis was not a frequent problem. If Professor Kerr's observations
were indeed drug related then the significance is that peritonitis
is not unique to formulations produced with toluene recrystallisation.
PB gave a report on the efficacy results from
the phase II study and concluded statistical power calculations
showed that 150 patients would be necessary to prove efficacy,
confirming our previous estimates from June 94.
A long discussion, which at times became moderately
heated, ensued. The meeting lasted for three hours. PL was "convinced"
that we had a "prima facie" case that toluene
was the cause of the problem and removing it would remove the
issue of safety and allow us to restart the intra-peritoneal studies.
(I am not sure whether by "prima facie" he meant
"on first impressions" or "cast iron", but
it sounded like the latter.) I said I hoped that the toluene was
the cause because it represented a "quick fix" and a
possible solution, but the onus was on us to prove it caused the
inflammation, show that its removal removed the inflammatory potential
and introduce the necessary manufacturing controls to ensure the
problem could not recur. Even in this situation, I said that it
would be very complex to restart intra-peritoneal studies, regardless
of the difficulty of negotiations internally, with clinicians,
the MCA and ethics committees we would need to obtain written
informed consent from a patient for a study whose only objective
was to look for toxicity with a compound that had previously caused
death. The ethical complexity of this is clear. I emphasised that
the situation with intra-pleural administration was completely
different. Pleurisy requires aspirin and resolves without particular
problems, peritonitis carries a 50 per cent mortality when untreated
or untreatable. I spelt out the pathophysiology. I was alarmed
that PL tried to deny the seriousness of the problem, tried to
differentiate between chemical peritonitis and bacterial peritonitis
(perforated duodenal ulcer or gall bladder are predominantly chemical)
and spoke of "peritonism" rather than peritonitis. "Peritonism"
is a clinical term to rather non-specifically define peritoneal
irritation. Peritonitis defines a clinical syndrome involving
hypovolaemic shock and high mortality. This conversation made
me think that PL was wilfully underplaying or ignoring the clinical
facts which we had at our disposal.
At the end of the meeting, for the second time
in 10 days, PL invited me to consider my position "over the
week-end" with the perceived threat that my job was on the
line.
During the afternoon Keith McCullagh asked to
see me. He was very soft in mood. He had obviously been briefed
by PL. He seemed to agree that intra-peritoneal studies would
be difficult and we should major on intra-pleural studies. However
he appeared to be convinced that "the toulene explanation"
was in the bag. He had spoken to Mike Wood. Mike Wood's own opinion
was very different. I told him that if toulene was the problem
and we could prove it then we may be able to restart the studies
although it would still be complex, however we still needed some
data and there were other possible causes. He did try in a not
too patronising way "but in my own interest" to advise
me that I should look for different ways of stating my disagreements
both with PL and himself. He also tried to explain to me that
PL and I had different objectives, PL's being to register a drug.
This in no way meant that PL was less concerned than me about
issues of patient safety or that he was any the less good doctor
than me. I concluded that PL and KM could only have been specifically
discussing this because PL felt that this may actually be the
case.
On 14 February a batimastat project team meeting
was held. PL did most of the talking and reiterated the "toluene"
story. Several people, particularly Alan Drummond told him that
it was not clear, not proven and other explanations were equally
plausible. During the meeting PL appeared to accet the logic of
not rushing back into an intra-peritoneal study. I specifically
did not say much as I have now made up my mind to avoid obvious
confrontation on these issues until they become inevitable, ie
until I receive a directive to actually restart the studies.
It is against this background that I saw the
intended draft press release, I believe for 17 February, which
is to be discussed at the non-executive directors meeting today.
The press release as it stands, says that toluene is the problem,
removing it is simple and the intra-peritoneal studies will restart
in May subject to regulatory approval. The supplementary notes
say that the problems experienced by patients have included "abdominal
discomfort and pain". This press release may be altered at
the meeting. I do not know if PL and KM believe it or if they
are playing a smart game of poker with the financial community.
To me they seem to be economical with the truth and taking unnecessary
hostages to fortune which are not in the company's best strategic
interests. My main concern though lies in the possibility of the
intra-peritoneal studies restarting without having definitely
fixed the problem.
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