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Volume 401: debated on Friday 14 March 2003

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Motion made, and Question proposed, That this House do now adjourn.— [Mr. Heppell.]

2.31 pm

I welcome the chance to put before the Minister my concerns about a clinical trial that took place in 1993 and 1994 in Southampton general hospital and other hospitals throughout the country. While some may think that there is no advantage in raking up history, some serious questions about the trial remain unanswered. Those questions are not only about the actions of Southampton general hospital, but cover wider aspects of the nature of clinical trials and how the safety of the public is safeguarded.

I was first alerted to this issue by a constituent, Dr. Steven Karran, who was at one time a member of the ethics committee at Southampton general hospital. At that time, I did what most constituency MPs would have done and wrote a number of letters about the subject. What then concerned me was that my letters to Bayer, the drug company, were not satisfactorily answered. A similar situation arose with regard to my letters to the Medicines Control Agency. Finally, when I asked the medical director at Southampton general hospital for an appointment to discuss the issue, I was passed from pillar to post, and to this day, that discussion has not taken place.

I should like to stress that that is highly unusual. In all other matters, staff at the hospital have been unfailingly helpful and they are usually only too willing to discuss whatever concerns I may have. Needless to say, I smelt a rat. Hence, I requested today's debate in the hope that the Minister would be able to obtain satisfactory answers where I have so far failed and that he would not be fobbed off as I have been.

I need to set this story in context, as some of the events leading up to the clinical trial in question are of great significance. I shall use the term "Ciproxin" to describe the drug throughout this debate. That is the easier-to-say brand name of a drug called ciprofloxacin, which is an antibiotic with a wide variety of uses. The drug is made by a company called Bayer.

The story starts in 1987. At that time, the ethics committees in Wessex were informed by Bayer that the Medicines Control Agency had issued a licence commonly known as a CTX for a 300-patient study of antibiotic protection in patients undergoing gall bladder surgery. The drug used was Ciproxin. The trial took place because Bayer was aware of something called the Flowerdew studies on a related drug, which had indicated a much higher than expected number of post-operative infections. It had also been shown that the blood levels of the drug were lower than expected, and that was thought to be the case because the drug had been administered at the same time as other pre-meds—drugs that are given in advance of a surgical procedure involving anaesthetics.

The drug company wanted to find out what effects the pre-meds had, so the licence that was issued was conditional on Ciproxin being given 60 minutes before the administration of any of the other commonly administered drugs that are routinely given on that basis.

The interval of an hour was determined on the basis of studies of Ciproxin in the blood. The drug was administered and blood samples were taken to establish the length of time it took before the drug levels in the blood were high enough to take effect. Delaying the administration of the pre-med for an hour meant that the drug had a chance to reach a level at which it was clinically effective. That is not the case when the drugs are administered together. Giving various drugs at different times before an operation affects the demands made of staff on a busy surgical ward. If all the drugs cannot be administered at the same time, the work load doubles.

The clinical studies showed that, when given well in advance of any other pre-med, orally administered Ciproxin can provide good protection from serious post-operative infections. Bayer published those results in 1989, and staff at Southampton and Glasgow were well aware of the results.

Now we reach the interesting part. In 1992, Bayer submitted a detailed protocol to the MCA to study the use of orally administered Ciproxin to prevent serious post-operative infections caused by elective or planned large bowel surgery. The septic risk of such surgery is five times greater than that in the previous study.

Professor McArdle, who is based in Glasgow and had been involved in the earlier research, wrote and designed the study. Bayer was also involved. There is no evidence of new studies that show the earlier study to be flawed. No evidence shows that the pre-med problem was anything but real. Yet the new study, which Bayer largely funded and supervised, ignored the known premed problem.

If the MCA was doing its job properly, it should have known about the pre-med problem. I have written to the organisation and its letter to me is a masterpiece of obfuscation. It claims that it was not allowed to provide information because it was given in confidence. We are considering a matter of public safety and interest, but we cannot find the answers or have proof of the study's findings.

I want to ask the Minister some crucial questions. Did the MCA grant a licence to Bayer in 1992 to undertake extensive clinical trials in elective large bowel surgery, using orally administered Ciproxin tablets to prevent post-operative infection? Did Bayer declare in its licence application the problem caused by the simultaneous application of other pre-med drugs? Bayer identified that problem in 1986, and it led the company to conduct a trial in which the antibiotic was administered before other pre-med drugs. Will the Minister undertake to let me see the application so that any shred of doubt about the trial can be laid to rest?

I am not sure who constitutes the villain of the piece. Is it Bayer through acting fraudulently? Is it the MCA, which made a mistake by letting the trial go ahead? Was somebody not on top of the job, and unaware of an earlier trial? I am not sure who is covering up for whom. Despite all the known doubts, the MCA issued a CTX to Bayer, granting it permission to undertake clinical research in 850 patients. That means that 850 patients will be put at greatly increased risk of contracting a severe post-operative infection.

There is some dispute. I have a sworn statement from Dr. Karran, who says that he has seen evidence that 46 per cent. of the 60 Southampton patients in the trial were adversely affected and contracted post-operative infections. However, in a letter to me, Bayer claimed:
"The results of the study as a whole also indicate that the rates of post-operative infections were similar between patients receiving ciprofloxacin … and those receiving the other, commonly used antibiotic combination. The rate of early post-operative wound infection, the primary goal of this treatment, were low and equivalent in both treatment groups."
I have not seen Dr. Karran's proof, but I am acutely aware that Bayer has been selective with its language in its letter to me. It cites only early post-operative wound infection. Clearly, other sorts of infection are associated with bowel surgery, but they have been specifically ignored. I also find it especially worrying that Bayer has not released the results of the research. Why not?

Before I became a Member of Parliament, I was a pharmacist. I was regularly inundated with drug representatives' glossy literature, which selectively quoted bits and pieces of the latest research that showed their product in a marginally better light than its competitors. This job can make one cynical, but I suspect that if the results of the trial had shown Ciproxin to good advantage, the research would have been published.

That raises another fundamental question that has a significant impact on public safety. Should the onus not be on drug companies to publish the results of any clinical trial, so that the information is in the public domain and can inform the wider debate? The answer that is always given is "commercial sensitivity". I understand the need for that in the short term, but the argument does not stand up in regard to the longer term. What price do we actually put on patients' safety?

Dr. Karran was on the ethics committee at Southampton hospital when the 1992 proposal was presented to the hospital in October 1993. He had been involved in the previous trial, and was therefore well acquainted with the potential problems of the proposed trial. Once aware of those problems, the ethics committee rejected the original protocol.

In an attempt to be helpful, Dr. Karran said he would be happy to support the trial if the Ciproxin was given separately from the other drugs. The professor in charge of the trial told the committee that the Southampton amendment would be followed by him and his research team. The study was therefore approved on the amended basis only. Bayer failed to act until June 1994. At that stage it admitted the existence of a potential problem, and informed all ethics committees of hospitals taking part in the trial except the one at Southampton. Why did it wait so long?

It may be asked why there was a problem if the protocol had been rejected. Unfortunately, in November 1994 Dr. Karran realised that the trial was going ahead under the rejected protocol of 1992 rather than the revised protocol of 1994. That was particularly serious because at the time most patients at Southampton received at least one of the pre-med drugs known to cause problems. A leaflet issued to patients undergoing the trial told them that they would be well protected against all post-operative infection—not just the wound infection that Bayer mentioned. Bayer denied that, but I have seen a copy of the letter given to patients. It says
"Either way you will receive medication with an active substance so that you are well protected against any post-operative infections".
Bayer also claims that it has a letter from the Southampton ethics committee giving approval for the original trial.

This is where it all starts to get a bit murky. Dr. Woodcock, who was secretary of the ethics committee at the time, wrote to the professor in charge of the trial at Southampton saying that the trial could go ahead subject to the necessary amendments. The professor wrote a letter in reply, parts of which were read out at an ethics committee meeting. Dr. Karran was under the clear impression that Bayer was happy to go along with the amendment. No one saw anything in writing at the time, but the decision was minuted.

It is alleged that Bayer contacted the professor in charge of the trial saying that it did not want to change the protocol, and could not proceed until the objections were released. Indeed, it is said that Bayer refused to supply the drugs until that was done. There is obviously a financial aspect, but I will be honest and say that it is not my major concern and I do not know what payments have been made and to whom. Anyway, the unamended trial went ahead somehow. Dr. Karran found out about it by chance in November 1994. The patients involved in the trial had all been informed in writing that the protocol had been approved by the Southampton ethics committee, which clearly was not true: the protocol used was the one that had been rejected.

That constitutes a major violation of the declaration of Helsinki—the European code of good practice. The first basic principle states
"Biomedical research involving human subjects must conform to generally accepted scientific principles and should be based on adequately performed laboratory and animal experimentation and on a thorough knowledge of the scientific literature."
That clearly did not happen in this case. The fifth principle states
"Every biomedical research project involving human subjects should be preceded by careful assessment of predictable risks in comparison with foreseeable benefits to the subject or to others. Concern for the interests of the subject must always prevail over the interests of science and society."
Clearly that principle was not followed either.

Bayer withheld critical safety information. It successfully deceived all other ethics committees in the UK and the Netherlands, as well as a number of physicians, nurses and pharmacists. Why did it all happen? It is often useful to consider motivation when trying to get to the bottom of a problem. Bayer's motivation is clear. Antibiotic cover for surgery was usually given by injection, which was costly and time-consuming. If the injection could be replaced by a tablet that was easy to administer, there would be a comparatively simple and cheap alternative—and the Minister knows as well as anyone the financial pressures on the NHS and our hospitals. There was huge sales potential if a licence could be obtained for oral use of the drug for routine prophylaxis. Hence the trial.

Unfortunately, the drug's potential was spoilt because it could not be given at the same time as other pre-med drugs, and the inconvenience to staff presented a major hurdle. There was, therefore, a huge incentive to try to establish a trial during which the administration of the drugs was not separated. Unfortunately, commerce appeared to win over ethics, with a drive to operate the trial in the manner that Bayer wanted rather than in the manner that the Southampton ethics committee had recommended.

The motivation of the senior medical personnel at the hospital at that time is less than clear. Medical trials are usually expensive and bring a certain amount of kudos, although, as I have said, I have not looked at that aspect of the case in depth. The motivation of my constituent, Dr. Karran, is clear. I have now known him for nearly three years, and his story has not wavered in a single detail. Quite simply, he wants the record put straight. The motivation of the senior management of the hospital is also unclear, but this appears to be one of those occasions on which serious doubts were raised by Dr. Karran, but not properly investigated. There has been an internal inquiry, but no one has really come forward. It is unclear whether the problems were financial, or whether there was a closing of ranks among a group of high-level staff.

So far as my motivation is concerned, I was originally helping a constituent, but, as time went on, I became intrigued by the lack of co-operation from some agencies and the lack of information coming from the Medicines Control Agency; there was an almost complete wall of silence. I then realised that the case could have wider implications, and that lessons could be learned that would be applicable to the many other clinical trials taking place at the moment. The MCA's behaviour in this matter does not inspire consumer confidence. The agency should protect the public from fraudulent and potentially misleading information, but it has clearly failed to do so in this case. Whether that was through incompetence or by deliberate intent is unclear. The public audit trail is non-existent, so it is almost impossible to get to the bottom of this matter. Do not the public deserve better?

I am also concerned about the actions of Bayer. As I said earlier, I believe that, in the interests of public safety, details of all clinical trials should be in the public domain. The current position is that the MCA has investigated its files but has repeatedly refused to disclose the relevant information, citing confidentiality and the code, although it has intimated in writing that the information provided by Bayer and McArdle in 1992 for the colorectal CTX was incomplete. We know that a licence was issued by the MCA, but one critical question remains unanswered. When making that application, did Bayer declare the problem caused by the simultaneous administration of other drugs used for the pre-operative preparation of patients? Does the Minister agree that, if Bayer did not declare the problem, its action was fraudulent and that some sanction should be taken against the company? If the problem was declared, will the Minister undertake to provide me with a satisfactory explanation as to why the MCA allowed the trial to go ahead, knowing the risk to the public? Who made that decision, and how could that person justify putting the lives of up to 800 patients at risk?

2.47 pm

I congratulate the hon. Member for Romsey (Sandra Gidley) on securing this important debate. The allegations about the Ciproxin trial at Southampton general hospital that we have heard today have, as she knows, been the subject of previous—and ongoing—investigations. She will understand that, for that reason, it would be inappropriate for a Minister to comment substantially on the case. I understand that Lord Hunt also declined to comment on the case in responding to a letter from the hon. Lady in May 2001.

The case has now gone on for some considerable time—since the beginning of the last decade, in fact—and to comment might prejudice any current or future proceedings. I also understand from correspondence that some of the issues raised in this debate have previously been investigated by the police, the General Medical Council, the Southampton university hospitals trust and, of course, the Medicines Control Agency. Because those organisations are best suited to judging the scientific and ethical issues raised by the hon. Lady, I am not prepared to say any more about the Ciproxin trial. However, an important question that arises from this debate is whether patients volunteering for clinical trials are adequately protected by the procedures and guidance that is currently in place.

I respect the integrity and sincerity with which the hon. Lady put her argument, but she will understand that the matter involves a considerable history.

I am aware that there have been investigations, but the problem is that the results are not in the public domain, so how can any member of the public be satisfied that due procedures were followed and that there was nothing fraudulent about the trial? I would be happy if someone showed me the information and said, "Here it is, Sandra. Go away and don't bother us any more." That has not happened, and we have come up against a brick wall.

What I will say is that I will attempt, within the law and within the practice of the House, to answer some specific questions as far as I can, although I remind the hon. Lady that I am treading lightly because this is extremely delicate ground.

First, what are the outcomes of the various investigations? Information on the police and GMC investigations has not been made public, and the hon. Lady is right when she says that. Southampton university hospitals trust has completed a thorough investigation and concluded that there is no evidence to support the substantive allegations made by Mr. Karran on the Ciproxin trial. Professor John Primrose is a senior consultant who was involved in the trial. There was a minor breach of research protocol, which was raised with Professor Primrose, but no further action was required.

Can the Minister say what the minor breach of research protocol is? If the breach is the fact that the wrong trial went ahead, I would not regard it as minor.

I can undertake to ask officials and lawyers within the Department, after the debate, to take a close look at some of the issues raised. I may be able to elucidate in a letter to the hon. Lady, but I must tread lightly on what is established precedent.

The MCA reviewed its records in April 2001, finding that the information that Mr. Karran alleges was deliberately withheld had been provided in another context. The agency concluded that there was no intention to mislead and that no further action was necessary. Mr. Karran has been informed of that on several occasions.

The hon. Lady will also know that, within administrative law and other areas, such decisions can be subject to judicial review and other matters, so remedies are available should Mr. Karran take issue with the conclusions that people have reached. However, I am not sure, on some of those issues, that the House is the right place to conduct, as it were, a forensic retrial or that a Minister in the Department should be involved.

The hon. Lady asks why the MCA has refused to disclose information on the clinical trials of Ciproxin to Mr. Karran. I say in response that the MCA has complied with the code of practice on access to Government information and has advised Mr. Karran of the relevant exemptions. The code provides for an internal review if individuals are dissatisfied with the agency's decisions. In addition, recourse is available to the Parliamentary Commissioner for Administration, who may decide to investigate complaints that information has been unreasonably withheld under the code. So, it may be that avenues could be pursued, but that is as far as I can go on this occasion on those issues, which have continued for some considerable time.

I return to what is an important issue: patient safety in clinical trials of this nature. The United Kingdom has long been regarded as a good place to conduct research. It is right that I put that on the record. A number of factors, such as the presence of highly motivated and educated investigators, a strong academic base, a comprehensive health service committed to research and development, well organised and funded medical research organisations and strong networks of general practitioners, have historically resulted in an efficient infrastructure for the conduct of clinical research. Many facets of that infrastructure provide protection for clinical trial volunteers. That protection has been reinforced in a number of ways since the Ciproxin trial.

The Government want to ensure that volunteers who participate in clinical trials are safeguarded to avoid any unnecessary hazards. In the United Kingdom, there are a number of safeguards in the present regulatory system, which I will describe in turn.

Does the Minister think that the 46 per cent. of patients who suffered post-operative infections in the trial were safeguarded?

I have said that I am not going to be pressed on the specifics. We have various agencies that are well placed to look into these matters. There have been a number of investigations. The nature of any such trial is, of course, a delicate and difficult matter. What I cannot do today is unpick an individual trial on an individual occasion. The hon. Lady knows that a number of trials take place every year with varying results.

The current system of regulation under the Medicines Act 1968 requires that anyone who wishes to test a medicine in a clinical trial must obtain a clinical trial certificate or an exemption from holding a CTC. Most trials in the UK are conducted under one or other of those exemption schemes. The MCA receives applications from companies to supply about 250 different medicines for clinical trials each year. It authorises about 800 commercial clinical trials and 1,000 non-commercial clinical trials. Studies in healthy volunteers are self-regulated under guidance from the Association of the British Pharmaceutical Industry and the Royal College of Physicians, but are expected to be regulated under the EU clinical trials directive, which I would like to mention later.

The application to the MCA must provide information on the medicine to be used, any non-clinical tests of safety, any previous clinical trials or results, or other clinical information about the medicine. The MCA's professional assessors subject any application to a robust scientific evaluation.

The Minister has just pointed out, rightly, that people applying for a trial must submit details of known problems. He said earlier that that clearly was not done in the Bayer case. Why is there not some sanction against drug companies that behave in that way?

I have outlined that there is a code of conduct. There is a number of avenues. Of course, the ultimate sanction is the law and our legal courts, inquiry by the police, as happened in this case, inquiry by the individual trust, as happened in this case, and inquiry by the MCA itself, as happened in this case. I realise that the hon. Lady raises these issues with integrity and because she believes that there are facts that need to be penetrated further. As she may know, I used to be a lawyer, but even so I cannot conduct a trial from this Dispatch Box. I am limited in how far I can go in this chain of inquiry—a chain that has gone on, I believe, for some nine years.

If the hon. Lady has questions other than those that were raised on previous occasions, she can raise them with my Department. Our officials and legal advisers will look into the matter and we will attempt to do what we can. However, once there has been an investigation by the various agencies, there comes a time, I am afraid, when the matter has to rest—other than judicial review or some other process that she may be aware of, but which does not occur to me on this occasion. This matter has been looked into, and the integrity of Parliament's intention to protect patients—

The motion having been made at half-past Two o'clock, and the debate having continued for half an hour, MR. DEPUTY SPEAKER adjourned the House without Question put, pursuant to the Standing Order.

Adjourned at one minute past Three o'clock.