E-drug: Good or bad clinical practice?
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[3 pieces from the Guardian(UK). First the editorial, then the
article and finally a background article on Clinical Trials.
Thanks to Charles Medawar for pointing this out to E-drug! WB]
Source: http://www.newsunlimited.co.uk
[which gives free access to The Guardian]
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Daylight on drugs: Americans are better protected. Why?
Tuesday July 27, 1999
The Guardian
The control of medicines in Britain has always been shrouded in
secrecy. Even when the last government produced its patient's charter,
which guaranteed every patient the right "to be given a clear
explanation of any treatment proposed, including any risks and any
alternatives, before they decide whether they will agree to
treatment", the secrecy of the regulatory process remained
uninterrupted. The 1968 Medicines Act, which makes it a criminal
offence for officials involved in licensing drugs to disclose
information about their decisions, remained in force.
In the United States, patients have a right to know why a new medicine
has been licensed, what type of clinical studies were undertaken, and
what detailed information exists on side effects. Here, all
information supplied to the Medicines Control Agency (MCA) remains
strictly confidential. Social reformers have long pressed for the MCA
to follow the open approach pursued by America's food and drug
administration.
Now we know something more fundamental is needed. Even the MCA is not
being provided with important facts. Our health correspondent reports
today on the disillusionment of two of the senior auditors whom drug
companies are obliged to engage to monitor the trials that all new
medicines are required to undergo to test their safety and
effectiveness. The MCA gets an auditor's certificate. It receives up
to 600 volumes of material for just one product. But what it does not
get are specific details on the conduct of the trials. The auditors
report that 43% of patients are not given clear instructions in using
medicines. In a third of the trials they found "significant
under-reporting" of side effects. The auditors want much more
systematic inspection of the trial process.
A voluntary inspection system already exists, under which drug
companies can invite the MCA to send in inspectors. But insiders
suggest the invitations are only issued when they are least needed. In
America, a cadre of FDA inspectors apply a much more systematic
approach. The European Union is considering a draft directive, which
would make inspections mandatory. Our powerful medicines industry is
opposed, but this is one issue on which Brussels must be backed. There
are two ways of improving drug safety and effectiveness: a more open
process (sunshine is the best disinfectant) and more systematic
inspections.
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Drug trials risk to patients
Audit shows flawed tests are a danger to health, scientists argue
Sarah Boseley, Health Correspondent
Tuesday July 27, 1999
The Guardian
Trials of new medicines to establish that they are safe and effective
are so badly flawed that they endanger the health of the patients who
take part and those who will take the drug once it has been licensed,
according to scientists who have been auditing them in confidence for
10 years.
Wendy Bohaychuk and Graham Ball are appalled at the poor standards
they have consistently found. "Frankly, after 10 years of detailed
auditing, I would never go into a clinical study myself and I would
certainly try to discourage anyone in my family from doing so," Dr
Bohaychuk writes in an editorial for the industry journal Clinical
Research Focus.
Problems she and Dr Ball have found include medicines being stored at
the wrong temperatures, patients not being properly informed of what
will happen in the trial, and the side-effects of new drugs not being
reported.
In a sample of 226 trials, they found that 43% of patients were not
given clear instructions for using the medicine. In 55%, there was
inadequate proof that the drugs had been properly stored: one patient
complained that a gel ran down his leg after it had been kept through
a hot summer in the doctor's attic. In a prostate cancer drug study,
the GP was not given proper instructions from the drug company on its
use on the grounds that it was already on the market. It was - for
treating high blood pressure. In a third of the trials, they found
"significant under-reporting" of side-effects.
On the basis of these trials medicines are given a licence, the seal
of approval for general use. But if they have been wrongly conducted,
says Dr Ball, we cannot be sure the drug is safe. "If the data are not
adequate, there is a risk to the patient who will be exposed to the
drug in the future."
The scientists' company, Good Clinical Research Practices, is called
in by pharmaceutical companies to establish whether trials meet
international standards. Drug companies are obliged to have an audit,
but not obliged to disclose the result to anyone. The audit
certificate that goes to the licensing authority - the medicines
control agency (MCA) in this country - states only that the audit has
been carried out.
Because of the secrecy surrounding clinical trials information, the
MCA and the government are in no position to know about the failings,
argue the auditors. "The government has no idea what is going on,"
said Dr Ball.
The doctors are concerned that patient safety is not at the heart of
these trials. "I think patients probably don't know what is happening
to them in the vast majority of cases. They are not adequately
informed. If they are informed, it is a biased information process,"
he said. "They are not aware that a clinical study is putting them at
risk."
The MCA admits that there is a problem. "The whole business of
clinical trials and good practice is down to a voluntary code," said a
spokeswoman. It has been invited by drug companies to do only about 30
voluntary inspections since 1997. But the EU is considering a draft
directive, which the industry is fighting, that would make inspections
mandatory. If that comes into force the situation could change
radically.
The Association of the British Pharmaceutical Industry said it would
expect members to adhere to guidelines on trials. It denied that there
were widespread failings.
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Trial and error puts patients at risk
Drug tests: Auditors claim that rules to minimise danger to human
guinea pigs are neglected
Sarah Boseley, Health Correspondent
Tuesday July 27, 1999
The Guardian
There are about 3,000 clinical trials in the UK at any one time,
involving hundreds of thousands of patients. But every one is a human
experiment, with risks attached.
There are rules to minimise the dangers to the human guinea pigs but
two auditors say patient safety is being neglected.
Those who take part in the first phase of clinical trials are usually
healthy volunteers, often students, who may be paid. The drug will
have been tested in animals.
Phases two and three trials are on patients with the diseases the drug
is supposed to treat, first a small group and then a large-scale,
often multi-national trial involving thousands. Those trials are
usually random - patients and their doctor are not supposed to know
whether they are getting the new drug or a dummy. The trials have to
be approved and overseen by ethics committees from the relevant
hospital or health authority.
Drugs may have unpleasant or harmful side-effects but Wendy Bohaychuk
and Graham Ball, whose company, Good Clinical Research Practices Ltd,
has been auditing these trials for 10 years, say patients are not
properly informed.
Andrew Herxheimer of the Cochrane Collaboration which trawls clinical
trials for evidence of what treatments work, said: "The implications
for the systemised review of randomised trials are horrible because it
means we cannot really trust them as much as we thought. We need far
more detailed accounts of exactly how trials are run."
Bohaychuk and Ball have put together a database from over 800 audits,
mainly from the UK.
They use checklists to ensure that patients had been asked if they
wanted to join a trial and told what to expect. They look for
signatures and dates on consent forms and check that the trial
documentation specifying what drugs the patient is on and at what
doseage tallies with the patient's notes - often it does not.
They divide compliance into grade I non-compliance - serious breaches,
which could create a dangerous situation for patients or allow an
unsafe product to get to market - and grade II - less serious but
still potentially unsafe.
Out of 226 sites (GP surgeries or hospital departments), they reported
in the journal Applied Clinical Trials that: "88% had at least one
event of grade I non-compliance, with an average of 2.3 events per
site. All of the sites had at least one event of grade II
non-compliance, with an average of 9.5 events per site."
At 31% of the surgeries or departments, they found "significant
discrepancies" between the patient notes and the forms for the trial
which should both have detailed the medication and tests the patient
was receiving. A further 31% had either no reports or inadequate
reports of serious side-effects of the new drug in 10% to 20% of
patients. At 55% of the sites, the medication was either stored badly
or there was no evidence that it had been properly stored.
In 81% of these studies, ethics committees were not told about all the
serious side-effects and in 31% they say "there was significant
under-reporting of safety information". In 37%, patients were not
asked to sign the consent forms until after the study had begun.
Dr Ball says he believed the problem was principally one of doctors
and drug companies cutting corners in their determination to prove
that a new medicine worked. "The pharmaceutical company is making
millions and the clinician is being paid thousands of pounds. It is
not wilful disobedience - it is just that people get biased in terms
of making money."
What starts as cutting corners could end up as fraud. Frank Wells and
Peter Jay of MedicoLegal Investigations have successfully taken 18
cases to the General Medical Council, the doctors' disciplinary body,
and have 12 more in the pipeline. Often the doctors involved were
quite good researchers, they say, but they had not got enough suitable
patients or enough time and so they made up data, assuming that they
knew what the outcome would be.
Mr Jay said: "Most patients will do exactly what the doctor says. The
vast majority of GPs are beyond reproach but every now and then we hit
upon one who is an outright rogue.
"I think they possibly start by cutting corners. They are expected to
recruit 20 patients and can only find 18 so they tell a patient the
ECG hasn't gone properly and have to run it again so they have got two
traces which they can use. It is very easy to fabricate it. Next time
they recruit 10 and invent 10. Next time they realise all they have to
do is fill in the forms."
The United States is the only country which sends in its own
inspectors from the food and drugs administration (FDA). Drug licence
applications will be thrown out if they do not come up to standard.
There is a lot of subtle pressure on patients
The fraudster
James Alfred Bochsler was a GP in Gipsy Hill, south London.
Twice in 1994 he signed deals to enter patients into trials for angina
and depression. His fees totalled �22,500.
He claimed to have enrolled 36 of his patients in the two trials, but
25 of the consent forms were forgeries, signed by Dr Bochsler himself.
One of the trials, for Solvay Healthcare, was for an anti-depressant.
One of the patients entered with a faked signature had twice been
admitted to hospital as a psychiatric patient while she was supposed
to be on the new medication under Dr Bochsler's supervision.
A second patient had been on other medication for lack of appetite and
constipation. None of those details was recorded on the forms that
went back to the company.
The second trial, for Bayer, involved a drug for hypertension (high
blood pressure) and angina. Dr Bochsler had been asked to take ECG
readings for the patients involved. For five pairs of patients, he
submitted identical printouts.
Dr Bochsler was struck off last November. "Scientific dishonesty
producing bogus results undermines the integrity of drug trials," said
John Ball, chairman of the professional conduct committee.
The investigator
Peter Jay of MedicoLegal Investigations
"We hear the most bizarre stories. There was a husband and wife in the
same depression study, which was a bit unusual in itself. The wife
clearly had a problem when I saw her. She agreed that she had signed
the consent form and taken the medication and her husband had too. I
said to him: 'What's your history of depression?' He said: 'I have
never been depressed in my life. Dr X told me that it would be in my
wife's best interests if I went into the study as well.' It was a
placebo controlled trial. The wife said the medication was bloody
useless. The husband said that for four months he had never felt so
ill."
The counsellor
Heather Goodare, counsellor to breast cancer sufferers and chairwoman
of Breast-cancer Research Ethics and Advocacy Strategy
"Patients are very vulnerable when they are being treated for cancer.
When you have just been told the bad news you are not in a fit state
to make sensible decisions. I think it is not a good idea to try to
recruit people into clinical trials at that point. There is an awful
lot of subtle pressure and people don't want to offend the doctor.
"I know of a patient who has spent five years on one cancer drug and
would be pretty grateful to stop it, but was asked to enter a study
into the longer-term effects. She thinks it is almost her patriotic
duty to enter the trial."
� Copyright Guardian Media Group
plc. 1999
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