Annex B
Chronology of BB events by project
BATIMASTAT:
treatment for cancer given by injection into
abdomen (tummy)
1994
13 October:
Memo from AM to 11 people including Keith McCullagh,
Peter Lewis and James Noble
"Intra-peritoneal adverse events and batismastat"
(Sunday Business) Advises of potential problems and need for caution
in studies.
October and November
Further report of peritonitis in batimastat
phase II studies
15 November
Press release
Batimastat starts phase III trials
November
Reports of peritonitis in phase III trials,
but some problems in control patients confuses picture
17 November
Project team meeting minutes (sent to Peter
Lewis)
"The current series of adverse events in
the clinic has led to questions. . . about the formulation."
"worthwhile looking for associations between
serious adverse events and different batches"
December
Informal agreement between clinical department
and investigators (doctors) to stop recruiting patients over Christmas
period until review at meeting on January 10
19 December
Project team meeting (sent to Peter Lewis and
Keith McCullagh)
"real concerns on the adverse event profile"
10 January
Meeting of London Gynaecological Oncology Group
with Drs Millar and Brown
Agreement to tentatively dose one or two more
patients with body temperature fluid"
17 January
Richards sells 112,568 shares at £5.25
McCullagh sells 111,700 shares at £5.25
John Gordon sells 30,000 shares at £5.25
Purchases of small number of shares (1,000-5,000)
by Raisman, Irwin, Lewis and Noble
18th January
Project team meeting minutes issued on 1 February
and contain no mention apart from occurrence of LGOG meeting,
or intra-abdominal problems—a bit strange that. They do
mention "warming". I suspect now that they have been
edited, I did not notice at the time.
(Events from here on chronicled in AM's self-defensive
notes to solicitor)
23 January
Telephone call at 9.00 am about further case
of peritonitis
AM informs Peter Lewis before board meeting
PL went home after board meeting without seeing
AM
24 January
AM telephones four doctors to tell them to stop
the study and leaves messages for two
25 January
AM sends letters to doctors to tell them to
stop recruiting
February
Some extremely tense meetings during which KM
and PL asked for immediate restart of study
AM frequently threatened with dismissal, but
refused to comply
17 February
Press release announcing stopping of study
Through rest of year there were various press
releases indicating batimastat was about to restart when AM considered
it should have been stopped and only finally restarted briefly
with a very small pilot study in a few patients using a much lower
dose (1/10) which still resulted in (mild) peritonitis
STOCK EXCHANGE
ENQUIRY FOUND
NO PROBLEM
Question "Who gave what evidence?"
Clinical department unaware of investigation
and not interviewed
MARIMASTAT
(treatment for cancer taken by mouth)
1995-96
Two press releases in December 1995 and May
1996 and subsequent share dealing in December 1995 by McCullagh,
Lewis and Noble are the subject of an SEC enquiry. AM advised
on both that they may contravene Medicines Act and FDCA (US equivalent).
The final press releases were very toned down compared to some
of the many circulating drafts. In addition the preliminary nature
of the data was stressed frequently by AM. I was repeatedly told
that we had to have a full and detailed press release under stock
exchange regulations. These were judged to be dominant by the
executive directors and I decided that the press releasese were
issued on their authority and responsibility, not mine. I remember
saying to PJL, "you guys are acting like the shares not the
drugs are our products"—"Well done Andy, you're
finally getting the picture".
December 1995/January 1996
I traded share options to a total profit of
around £300,000 after PL and JN traded theirs.
1996
April/May
Clinical department planned and proposed a "Potentially
pivotal phase II dose comparison in pancreatic cancer"—study
128. The executive directors wanted it to be called phase III—after
much discussion (and delay) and an increase in size from 300 to
400 patients the FDA agreed that it could be called phase III.
November
Preliminary evidence from pancreatic cancer
study 128, which was inconsistent with optimism, this evidence
continued and strengthened throughout 1997 and I kept PJL informed
until May.
We heard from DDMAC (FDA division) that they
took exception to our press releases. They informed the SEC and
we were notified of the SEC enquiry some time in March 1997. I
was asked by Paul Littlewood to be the first to attend. I was
very surprised as I thought this was the executive directors'
responsibility. Virtually the only contact I had from the directors
on this was from Peter Lewis: "Remember Andy, united we stand,
divided we fall". Paul Littlewood dismissed it as a routine
matter. I took a different view.
1997
February
AM reprimanded for "attempting to demoralise
senior management" after warning an R&D strategy meeting
that we should not plan on a registration based on the pancreatic
cancer study.
June
Data inconsistent with outcome of pancreatic
cancer study sufficient for registration.
18 June
Send memo to KM re marimastat programme. "it
appears that current corporate strategies assume a high probability
of success for these trials. However, it is necessary to plan
for a finite risk of failure. I recommend a corporate direction
which includes the possibility that marimastat may be an effective
therapy, but efficacy may not be demonstrated until after the
turn of the century."
December
Data suggests possible better effect of higher
dose.
30 December
Request to FDA by Greg Hockel on my instruction
for permission to perform interim analysis.
8 January
Memo from Greg Hockel about "furore"
from executive directors over request—concern over leaving
"a legal paper trail about data".
14 January
Three line fax from FDA approving request to
have unblinded interim look at data.
Throughout January and February AM continues
to recommend interim analysis in best long-term interests of drug
and company—executive directors refuse.
ZACUTEX (LEXIPAFANT)
(treatment for pancreatitis)
1994
28 March
Memo from AM and Lloyd Curtis:
"minimalist approach . . . provide a basis
for an application for a marketing licence which could be shored
up at the appeal stages by new data from (other) trials".
May
Lewis overrules Millar and Curtis on need for
a dose comparison study after intense debate. Millar and Curtis
warn that this will give regulatory and commercial liability,
but finish up shrugging shoulders and accepting written ruling.
(This later becomes major objection of EMEA).
23 June
First protocol of study 214 (UK study) issued
as "A phase II . . . study . . ".
17 November
Protocol title changed to "Phase III"
at request of executive directors without change in study design.
21 November
Press release to announce start of Phase III.
1996
13 September
Main analysis of 214 in favour of Zacutex but
not statistically significant (becomes major objection of EMEA.
Peter Lewis "That's it, we're cratered".
September
Re-analysis by clinical department (becomes
major objection "data reconstruction"—and "sub-group
analyses" EMEA aka "data-dredging").
30 September
AM says to McCullagh (verbatim from memory).
"I think the drug works but we do not have absolute proof.
It can form the basis of an MAA, but you must tell me you can
live with it being rejected before we make it". McCullagh
agrees.
October
AM careful to fully inform new incoming commercial
director Pam Kirby of the full history of design of 214, the Zacutex
programme and the data so that "if the MAA is rejected she
will understand that AM is not an incompetent Director of Clinical
research".
November
Computer programmes for reporting preliminary
data from US study (215) for the data review committee show a
pattern inconsistent with 214. Millar unblinds mortality data
and sees a preliminary pattern not suggestive of the same treatment
effect as in 214. This ultra-inside information shared with Peter
Lewis only. No-one else is informed, PL says he will make sure
the company's plans are appropriately handled in view of the pessimism—don't
tell Keith, he won't be able to take it. I am massively busy with
preparing MAA and getting marimastat programme off the ground.
December (? November)
? Company issues up-beat press release against
AM's advice. (I can't find this!!!)
1997
February and March
Data from 215 continues to give pessimistic
picture. AM informs PL on a regular basis of ultra-inside information.
AM says he can't understand the business plans of PK and KM. The
KM-PK axis is becoming very strong. PL and AM become "marginalised".
PL says he had told Keith of the implications of the data but
"he won't listen". I keep the data to myself to preserve
the integrity of the study.
February
AM reprimanded for "attempting to demoralise
senior management" after warning an R&D strategy meeting
that we should not plan on a definite registration for lexipafant
(and, at the same time) positive data from study 128
Noble quits
Unknown to AM, Peter Lewis arranges with KM
to exit company.
March (? April) (I can't find the press release)
Lewis trades shares (? £600,000).
April (? date)
Data review committee convened and report low
event (mortality) rate and recommend increasing size of study
(and in view of data from 214) changing to a mortality study.
7 and 8 May (Wed and Thur)
Preliminary EMEA responses received in house,
but regulatory department instructed on "pain of dismissal"
not to disclose. (I now understand that PL sent a memo to KM warning
of pessimistic nature of responses).
Events from here on in May are partly chronicled
in document written on 8 July and given to Mairi Eastwood to assist
in rebuilding relationship with KM
9 May (Friday)
AM enquiries about EMEA response and told they
are due next week
AM is shown a press release on clinical data
of 214 to be issued at same time as presentation of data at a
conference. AM recommends not to issue the release in view of
the regulatory process, but is informed he has no right of veto.
AM signs for "medical correctness" AM is not shown the
other press release "New appointments to support transition
to an international operating business" authorised by KM,
PL, PK, Paul Littlewood and Katie Arber.
11 May (Sunday)
AM telephoned at home by KM at 5.00. KM says
there are major objections by EMEA. AM not surprised by objections,
but asks when we received it "Late on Friday evening"
replies McCullagh. AM asks if the press release (single one about
clinical data as AM thought) be stopped. "No" says McCullagh
"already on wire". Arrange to meet next day.
12 May
KM tells me Lewis will be leaving company. Millar
suspects treachery. KM denies any knowledge of reason for pessimism.
13 May
I personally inform KM of state of data of 215
(and marimastat study 128). KM says he will fire PL. PL never
returns to full-time work, but he is also never fired.
14 May (Tuesday)
KM says he has to wait until board meeting (21)
to fire PL. I learn of FT article "BB set for drug launch"
and "These are momentous days for BB". I learn there
were two side by side press releases. I start attempting to get
the company to correct the misleading impression. KM almost agrees
over the next few days, but finally in agreement with Paul Littlewood,
AM Kirby and Katie Arber, he refuses to do anything. Apart from
being dishonest I argue this will give us a liability for a shareholders
action in the probable event of a failure of lexipafant. (I did
not actually know at that time it was a crime to mislead the stock-market,
but I knew it was dishonest and it certainly seemed unadvisedly
risky from a business point of view). The arguments went on all
week.
15 May
KM said "These allegations you are making
against Peter Lewis are very serious—would you be prepared
to back them up in court? I said yes and gave him every bit of
"ultra-inside" clinical information in writing.
19 May
Met with KM and John Raisman to prepare for
board meeting. I kept reminding Keith that things were not as
optimistic as he said.
21 May
I presented to the main board and stated the
estimated probability of success of MAA at time of submission
was 40 per cent. PK was furious and after board meeting denounced
clinical research as complete mess. KM supported her.
22 May
KM recommended to do more pancreatitits studies,
I argued strongly against and put it in writing the next day.
30 May
I get number from Barbara Quinney and phone
John Raisman at home (no written record) and query Peter's dismissal
and business plans in relation to clinical data. He tells me that
what Peter did was despicable, but the company cannot stand scandal
of firing him. He knows Keith is very optimisitc but he has great
confidence in him.
End of May (?date)
Met with KM and PK to discuss ultra-inside information
and actins on 215, we agreed to go for 1,500 patient study. I
told them chances of success were at best 60 per cent, maybe lower.
12 June
Memo to KM saying I could do no more corporate
presentations on this business plan. I would continue to discharge
my duties in clinical research.
At various times I discuss the data and situation
with Alan Drummond, but am wasting my time—he is so ineffectual.
30 June
Lewis steps down from board for family reasons
and sells all shares—no announcement.
7 July
First meeting with Mairi Eastwood (management
consultant) to attempt to repair relationship with McCullagh and
achieve technical input to the decision making process. Raised
permission from Paul Littlewood to disclose confidential information
and he authorised payments. I prepared written document to give
information to brief Mairi (not to act as legal document).
July/August
Mairi gave me rules to follow, which basically
meant avoiding the issues. I stopped arguing with Keith and Pam.
People in my department told me I was happier and that I could
not do anything about it anyway—Keith was the boss. On 19
August, I informed Tony Weir of my position with regard to my
views on Lexipafant and sold £200,000 worth of shares and
options. In effect, I was betting against the board. I knew that
the search for a "big-hitting" supervisor for me was
continuing.
September
KM asked me to get a CRO in to help with recruitment
to 215 (already going extremely well). This would cost about £2
million, give me massive logistical laxity and probably not help.
I could not understand it. It seemed like part of an attempt at
laying a paper trail to show "confidence". I unblinded
the mortality data and saw no difference between Zacutex and placebo.
Probability theory shows the chances of the drug working are miniscule.
I recommend a data review. KM refuses and says he wants a CRO.
I see Fallen, newly appointed and try to explain to him that KM
is attempting to waste money. Fallen lectures me on "integrity"
and says "remember Archie Norman" (I thought he was
a surgeon!!!). I also remonstrate.
11 and 12 September
I have stern arguments with McCullagh and he
gives me written warning about GCP and not to discuss project
related matters with executive directors.
September through December
Continue to recommend data review at every possible
opportunity. I put it in writing in December, despite knowing
Keith's opposition to it.
Jensen joins and we review data as treatment
AB and C, (Jensen thinks this does not "unblind"). I
believe it is obviously incompatible with any treatment effect,
I recommend a data review in writing.
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