[Pharm-policy] UK: Bayer in Illegal Drug Trial

[Mike Palmedo]

KEYCODE BAYER #27

KEYCODE BAYER is published by the German group BAYERwatch which has been
monitoring the BAYER Corporation for
more than 20 years.

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UK: Bayer in Illegal Drug Trial Scandal

Over 300 unsuspecting patients in hospitals across the UK were subjected
to experiments of a new application of the Bayer drug
Ciproxin with which the company wanted to enter the highly lucrative UK
antibiotics market. A senior hospital consultant in
Southampton, Steven Karran, who had carried out extensive studies of the
effects of Ciproxin on patients undergoing large bowel
surgery, warned Bayer clearly of the dangers of this drug. Bayer ignored
these warnings for over two years. "The Bayer ciproxin
trial in Southampton, of which I have first-hand knowledge, was
scientifically, clinically and financially fraudulent. It exposed
patients to serious risk of infection and violated their basic human
rights", Karran says. Karran´s warnings were backed up at the
time by another member of the Southampton Hospitals Trust´s Ethics
Committee, John Whale. 

After five years Bayer is still keeping the trial results secret and
obviously fears prosecution. Normally drug trial results are
published within a few months. Recently an MP demanded a clear statement
from Bayer about the unapproved trial. A senior
research scientist at the company´s headquarters in Newbury, Dr. James
Parker, tried to fob off the enquiry by telling the MP she
was "misinformed" that patients were offered full protection when Bayer
asked for their consent for the experimental use of the
drug. This, even though the patient information sheet stated clearly,
"you are well protected against any post-operative infections". 

Bayer gave false information to the Medicines Control Agency when
applying for a certificate to try out the new application of its
drug. Bayer already knew through research it had sponsored at Southmead
Hospital in Bristol that Ciproxin would be ineffective in
preventing infections because of dangerously diminished absorption and
interaction with premedicants.

The surgeon Steve Karran who acted as whistleblower has lodged an
affidavit stating that he warned the responsible managers at
both the company´s headquarters in England and Germany and the Hospitals
Trust of the serious dangers to patients. Instead of
stopping the trial the Southampton Hospitals Trust hounded him out of
his post for misconduct and it was only after Karran
appealed to the GMC that he was reinstated. A senior consultant, John
Primrose, who was an accessory to Bayer´s illegal
experiments and currently under investigation by the CID on manslaughter
charges continues to practise. Bayer has not been
prosecuted, has paid no compensation to relatives of patients injured or
killed in the course of its unapproved trials and is still
keeping the results under lock and key.

Reports on aspects of this serious malpractice by Bayer and a number of
consultants in Southampton, Glasgow and other hospitals
throughout the UK appeared in the Mail on Sunday (Martyn Halle) and
Sunday Times (David Leppard, Insight Editor). 

INTERVIEW WITH DR STEPHEN KARRAN

How and when did the problems with the Bayer antibiotic ciproxin become
evident?

In 1993 Bayer submitted the trial protocol for approval by the
Southampton Hospital Trust Ethics Committee. At that time I was
Reader in Surgery at the University of Southampton and member of the
Ethics Committee. 

Professor John Primrose had "brought" the Bayer study with him from
Leeds and wished it to be extended to patients in
Southampton. 

I had serious doubts as to the scientific and clinical validity of the
Bayer ciproxin trial. In a previous protocol submitted by Bayer in
June 1992 there had been problems with ciproxin because of diminished
absorption. For marketing reasons Bayer was keen for
the drug to be given orally to the patients in the U.K. trial (Note:
when given prior to an operation in Germany, ciproxin is always
given intravenously to patients undergoing large bowel surgery – in
other words, Bayer was willing to put British patients at risk by
using the drug in a way which would be illegal in Germany.)

Three groups of drug commonly given to patients before major surgery
interfered with the absorption of the Bayer drug ciproxin.

Secondly, the comparator suggested by Bayer was a standard drug for the
proposed application but used in a sub-optimal dose.
The comparator proposed by Bayer was cefuroxime. The using timing is
three doses in a twenty-four hour period. Bayer gave only
one dose over twenty-four hours and referred to results obtained from a
Glaxo study with Clafuran (Roussel). However, Bayer`s
quoting this study in this connection was fraudulent because this was a
different drug.

Another problem emerged two years later. An investigator enquired
whether patients would be concurrently taking part in any
other study (anticancer drugs and radiotherapy simultaneously).

Bayer informed the investigator that this would be acceptable.

This was clinically fraudulent according to General Medical Council
(GMC- doctors`and surgeons regulatory body) and would not
have been passed by the Ethics Committee. As is customary in such drug
trials, Bayer promised patients taking part full protection
against post-operative wound infection but they were in fact exposed to
a real risk of developing infections i.e. their basic human
rights were violated in that they were given unapproved drugs and were
also deliberately deceived by Bayer into giving consent to
the trial under false pretences. Medical staff who queried giving
ciproxin in this way to patients undergoing colorectal surgery were
assured by Bayer that the drug and procedures used had been approved by
the Ethics Committees and the Medicines Control
Agency. This is untrue.

I have seen the trial results for the seventy patients who took part in
the Bayer trial in hospitals under the Southampton Hospitals
Trust and they show clearly that nearly half of the patients developed
post-operative wound infections requiring "rescue therapy"
i.e. emergency therapy.

Bayer`s actions represent a major criminal assault on the patients who
took part in the ciproxin trial.

When did it become clear that there were problems with ciproxin?

The problems arose through the nature and design of the Bayer trial
rather than the drug itself. Bayer was aware of the absorption
and interaction problems two years before the ciproxin study was
designed through studies carried out by Professor Reeves in
Bristol. Bayer sponsored the work at Southmead Hospital to acquire data.
When the company discovered that the results of the
preliminary studies ("assay work") were likely to have a negative effect
on sales of ciproxin, it simply decided to suppress and
ignore the results.

In what ways do you think Bayer is at fault?

Bayer has acted fraudulently in several ways: firstly in terms of the
scientific validity of the trial design – the study was scientifically
flawed from the outset; secondly clinically in terms of their treatment
of the patients taking part, who were deceived by Bayer into
giving consent and furthermore had no proper protection against
post-operative wound infections; thirdly in my view the company
has acted unethically in spending vast sums of money – well over half a
million pounds – in attempting to "bribe" members of the
medical profession to act unethically, that is, Bayer has compromised a
large number of professionals by assuring doctors that its
methods and procedures were ethical when infact it was well aware that
this was not the case.

Do you have any comments on Bayer`s press release of 26th May 2000?

The statements made by Bayer concerning the ciproxin trial are evasive,
untruthful and deliberately misleading.

Are there any up-to-date independent reports on the use of ciproxin
against post-operative wound infection in large bowel surgery?

There is no other research to date which might indicate that this is a
false alarm. Bayer should have untertaken further research if it
was not satisfied with the outcome of ist original studies. In the
absence of such further studies the research results originally
obtained must be regarded as valid. In June 1992 Bayer knew of the
problems of diminished absorption and interaction with
common pre-medicants of the Bayer antibiotic ciproxin when administered
by mouth but did nothing for a least two years to
protect the lives and well-being of patients. It was not until June 1994
that Bayer admitted the existence of an absorption problem
and rewrote the ciproxin trial protocol accordingly. Since that time
ciproxin has not been administered orally to patients in British
hospitals for the prevention of post-operative wound infections after
large bowel surgery.

Are all the trial results freely accessible?

No. Bayer has refused to disclose the results on spurious grounds of
confidentiality. Consultants and doctors who participated as
investigators are also keeping quiet.

What are the problems connected with the Bayer ciproxin trials in
Southampton?

The Bayer ciproxin trial in Southampton, of which I have first-hand
knowledge, was scientifically, clinically and financially
fraudulent. I compromised the integrity of the University, the NHS
Hospitals Trust and the individual doctors involved. It exposed
patients to serious risk of infection and violated their basic human
rights: real physical harm was done to patients who were
deceived by Bayer and ist representatives into believing that they would
be fully protected against post-operative wound infections
throughout the duration of the study.

(See patient information sheet) The Bayer company and the consultants
and doctors who took part in the ciproxin study have
entered into a conspiracy to draw a veil of silence over the whole
matter. In my view Bayer`s behaviour and that of certain
consultants who knowingly deceived patients, exposing them to
potentially fatal infections warrant to pressing of criminal charges.
One consultant who was Head of Surgery at the relevant time in one of
the Southampton hospitals is now being investigated by the
CID on a manslaughter charge.

Were the hospitals taking part in the ciproxin trials warned of possible
risks to patients involved?

Yes, in October 1993, by me. To the best of my knowledge, I was the only
person to draw attention to the serious dangers posed
by the oral administration of the Bayer drug ciproxin to patients
undergoing colorectal surgery. I know that the Glasgow investigator
was aware of the dangers to patients from post-operative wound
infections but both he and the consultant Head of Surgery at
Southampton, Dr. John Primrose, chose to remain silent about the risks
involved.

There was also an investigator at the Dutch centre involved in the
ciproxin trial, a hospital in Rotterdam, who knew of the risks but
also chose to remain silent.

Did Bayer take yours objections to ciproxin and the timing and method of
its use seriously?

Not at the time. Later they admitted that there was a grave problem and
SIX MONTHS LATER they rewrote the trial protocol
BUT this was only because I had lodged an official complaint – they did
not act of their own volition. They took action to change
the protocol in June 1994 but the amendment did not appear in the
protocol until December 1994. At this point the Bayer ciproxin
drug trial had been running for over TWO YEARS:

How did the Health Service Trust react on being warned of likely
problems and hazards for the lives and well-being of patients in
their care?

The Southampton Hospitals Trust initially refused to investigate.

In January 1996 I made a formal request to the Health Sevice Trust to
enquire into the activities of the Bayer company and the
medical staff involved in the ciproxin drug trial. The Trust refused to
take action but initiated disciplinary action against me in
January 1996 at the request of the Head of Surgery, Professor John
Primrose, for reporting the matter.

It was in fact only through a chance conversation with the
investigator`s research nurse that I had learned that Bayer and John
Primrose were proceeding with the ciproxin trial in Southampton on the
basis of the original unamended (and therefore faulty)
protocol which Bayer wished to retain to optimize the sales chances of
the drug ciproxin. I should note that the grave medical
malpractice perpetrated by Bayer and certain consultants in Southampton
was corroborated at the time by a former policeman and
fellow member of the Ethics Committee, John Whale. (See report by Martyn
Halle, "Mail on Sunday" 8.8.99 "..70 patients at risk"
and David Leppard "Sunday Times" "Bayer company put patients at risk in
hospital trials").

Are the serious problems which have arisen in the case of the Bayer
ciproxin trial typical for hospital drug trials by pharmaceutical
companies in general or has Bayer behaved differently from competitors?

In the eight-year period I sat on the Southampton Hospitals Trust Ethics
Committee we dealt with over 200 applications, adding up
to a total of over one-thousand six-hundred drug trial applications: I
have never experienced anything remotely similar to the Bayer
case with the antibiotic ciproxin. If a protocol or drug is faulty the
investigators and the company involved are refused permission to
go ahead and accept the decision of the Ethics Committee: Bayer and the
investigators involved in the ciproxin trial ignored the
decision of the Ethics Committee and went ahead with an unapproved drug
used in an illegal manner.

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