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KEYCODE BAYER #27

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. Karranïs warnings were backed up at the time by another member of the Southampton Hospitals Trustïs 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 companyïs 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 companyïs 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 Bayerïs 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.