A RAY OF HOPE
Transcript UK BBC Documentary
Panorama London, March 1996
Retrovir, the drug better known as AZT, is a billion pound success for
a British drug company. But can it do more harm than good? Tonight, Panorama
reports on the controversial drug sold as a ray of hope.
In 1985 Bob Threakall was told he had HIV - he was one of 1200 British
haemophiliacs infected by contaminated blood. Like most others he continued
to feel well, and expected to live for many years before developing AIDS.
In 1989 his doctor put him on AZT even though he'd had no symptom of
AIDS. An American study had been published encouraging patients not to
wait, but to start taking the drug early in the hope of prolonging life.
But Bob Threakall found that after he took AZT his health started to
Bob Threakall: "I am very glad that Sue's here because there
isn't a lot I can actually do without making myself breathless and that
sort of thing."
Sue Threakall: "He gradually began to lose more and more
weight, then he began to get lots of minor infections."
Bob Threakall: "I was actually diagnosed HIV positive in
the sense that..."
Within 18 months of starting AZT Bob Threakall was dead. His widow maintains
it was the drug that killed him, and she's suing the manufacturer.
Sue Threakall: "I'm totally convinced that the things he
was suffering from were the side effects of AZT... If you look at the known
documented side effects of AZT there is a similarity between those, a very
strong similarity between those and the symptoms of full blown AIDS."
Graham Ross: "Trial in about 18 months time..."
The lawyer bringing the case will rely on Bob Treakall's medical records
to support the claim that it was the drug that killed him not his disease.
Graham Ross: "There was never a diagnosis of AIDS at any
stage. The form of pneumonia that is on the death certificate is not AIDS
associated pneumonia. It was bronchopneumonia. The basis of our claim is
that it was AZT that caused that damage, that is going to the whole issue."
Fears of side effects of AZT have led many patients to oppose its use.
Some activists maintain that its to toxic it can kill. And yet the same
drug was recently hailed as the centre of a breakthrough against the AIDS
Newsman: "...the biggest ever study into AIDS treatment..."
At an international scientific conference in Denmark it was announced
that cocktails of drugs each based on AZT could attack HIV and prolong
life. And AZT's manufacturer is recommending to patients that once again
they should not wait, but start taking the drugs early while they're still
well in the hope of delaying the onset of AIDS.
Dr. Palmer: "I think the answer is very simple and that
is, treat as early as possible in patients who have been diagnosed as being
HIV positive... hit it early, hit it hard."
But is it really so simple? The recent history of AZT might suggest
greater caution. Over the past decade clinical trials have tested the drug's
long term effects and there have been clashes between the manufacturer,
Wellcome, based here, and independent medical researchers over what the
results show. Is AZT as good as Wellcome claims? Or as dangerous as its
Panorama has investigated how the company dealtwith some uncomfortable
evidence - its story which reveals a potential collision course between
the pursuit of profit and the search for truth. AZT was first tested where
panic met affluence - in the United States a decade ago. Among gay men
in San Francisco and other cities the sudden presence of mass death set
of a desperate search for treatments. Scientists at Wellcome's US laboratories
found that a failed cancer chemotherapy agent inhibited replication of
the AIDS virus. It was azidothymidine, AZT.
Dr. Barry: "Our senior laboratory technician that we had
worked with for a long time came to my office and said, David I think we
have it. And she showed me her laboratory results which showed that the
virus had been completely inhibited."
Wellcome patented this breakthrough. In 1986 the company set the first
controlled clinical trail of AIDS patients in eight American cities. Half
were given AZT, half got an identical looking blank or placebo. The plan
was to study them for six months but there were dramatic results only after
four months and the trial was stopped early. Among patients taking the
placebo there had been 19 deaths. In the matching group taking the real
drug there was only one death. AZT worked at least short term, but as for
the long-term an important minority had doubts.
Dr. A. Abrams: "We do know that AZT's benefit is short lived,
and that if the study had gone too much longer then maybe that benefit
that was seen at that point in time could have disappeared. So to say that
taking the drug prolongs survival compared to taking the placebo I think
was premature, because the study was too short."
And yet officials waived the usual requirement for a second clinical
trial. The company worked at record speed with the Food & Drug Administration
to prepare data for an approval hearing on Wellcome's application to sell
AZT for AIDS patients. But this fast track was little too fast for the
Dr. Itzhak Brook: "I had serious doubts whether we had all
the information we need upon toxicity, about the dose, about even how effective
it was and I felt we needed a few more months to get answers from the company."
Dr. Barry: "...whether I agree with him or with you about
The transcript of the Hearing released to Panorama shows that Dr. Barry
said Wellcome viewed any delay with great chagrin. We have invested more
that 80 million dollars in the program so far. It has been a tremendous
burden to us, he said. We would definitely prefer not to continue that
program as it is for any significant period of time.
Dr. Brook: "Well it was harsh reality type of approach.
Here we were asking for science to protect the public and the answer was
you have to consider our financial situation. If you don't approve it today.
I'm not sure we can sustain the research of this drug, that was the implication.
It was like telling us approve it now or never."
Reporter: "He thought you were saying, approve it now or
never. Is that right?"
Dr. Barry: "I have no idea of what Dr. Brook thought."
Reporter: "Was that what you were saying?"
Dr. Barry: "No"
Reporter: "Then what were you saying?"
Dr. Barry: "That it was much better to approve it now than
later, for everyone. For the company and particularly for the patients."
Reporter: "So when you said, we would definitely prefer
not to continue and we look at this with great chagrin..."
Dr. Barry: "Yes..."
Reporter: "...that wasn't in any sense putting pressure
on the committee to approve now."
Dr. Barry: "Of course I wanted pressure on the committee
to approve now, that was not a threat, when I said we definitely prefer
not to continue the program if the FDA and its committee had said, well
though Dr. Barry you'll have to do it, we'd have done it."
Reporter: "But you were consciously putting pressure on
the committee for a quick approval?"
Dr. Barry: "Yes, of course."
It worked. The drug was approved with only the Chairman voting against.
Wellcome promoted the drug to doctors under its trade name, Retrovir.
Woman Promoter: "Retrovir is a major step forward. Our first
weapon against this deathly virus. However, its only the beginning - a
ray of hope for us all."
The company says it was hurrying to get help to patients. Wellcome set
the initial cost of a year's supply of its ray of hope at ten thousand
dollars. Its shares were already rising - after the approval hearing their
price more than doubled.
Once Wellcome could sell AZT in 1987 its potential market across the
United States and worldwide was perhaps a hundred thousand people living
with AIDS. But just over the horizon was a much bigger prospect - millions
of people infected with the virus but with no symptoms. If they could take
AZT, it could become one of the great pharmaceutical jackpots - an expensive
drug sold year after year to people who aren't ill.
People infected with HIV could expect to live for years before developing
AIDS illnesses. So for them fears of AZT's long term dangers were important
- they might take the drug for years. And some patients in the early trials
of AZT found its side effects appalling.
Keith Kroebbel: "I think that AIDS drugs are not like what
we're accustomed to thinking of as medicine. We think of antibiotics. AIDS
drugs are chemotherapy, nasty nasty stuff, it really hurts your constitution,
you've got your bone marrow cause the anaemia."
Randy Vielbig: "I also received two transfusions, two of
the AZT, I have AZT related anaemia to this day even though I'm on a low
dose of AZT at this time."
Reporter: "What did you feel?"
Kroebbel: "As if I had been poisoned. Very very seasick,
it wasn't a throwing up kind of nausea, it was a seasickness that was in
my bones. And headaches, inability to concentrate or respond."
Reporter: "How long did you stay on AZT?"
Kroebbel: "I was on it I think just about exactly 18 months."
Reporter: "And what happened when you stopped?"
Kroebbel: "I felt great. I felt so much better, that's when
I stopped because I was going on vacation."
For the American government scientific adviser on AZT the drug's long
term toxic effects were of major concern.
Dr. Ellen Cooper: "If the efficacy of the drug wanes or
lessens over time and there are toxicities that aren't apparent at the
beginning, most subtle toxicities that accumulate over time, there may
come a point where there's more, the drug does less good than it does damage."
Reporter: "And what did you know about those long term effects
at the moment the drug was approved?"
Dr. Cooper: "We really didn't know anything."
Dr. Cooper has told Panorama that she wanted a long term study of the
drug among patients with no symptoms. But there was no long term study,
The company and a team of researchers set up a trial notionally to last
three years, but designed so that it might stop early if it found even
a modest short term benefit.
Reporter: "Did you think that that was a good thing or a
bad thing to do?"
Dr. Cooper: "I thought that it was not a good thing to do."
Reporter: "So why did it happen?"
Dr.Cooper: "Because other people disagreed with me."
Dr. Barry: "We surmised that if it delayed the onset of
symptoms by say a year eventually it would delay their death by approximately
that same period, say a year."
Reporter: "That was what you hoped and assumed?"
Dr. Barry: "That's what we believed overall in looking at
all the data we had."
And as Dr. Barry anticipated this trial, codename 019, was stopped early,
after studying patients for just over a year. Eight in a hundred on placebos
had developed the first symptoms of AIDS. But among those taking AZT only
four in a hundred had these symptoms. The US government, which had sponsored
the trial, acted as cheerleader.
Louis W. Sullivan: "This finding underlines anew the need
for people to voluntarily undergo HIV testing and counselling. We are indeed
entering the period when AIDS may become a treatable disease."
But while taking AZT early was found to delay the onset of some AIDS
symptoms, it was still not known if it could ultimately prolong life. The
study stopped too soon to tell.
Dr. Cooper: "Its tempting to stop trials early, there's
no question, certainly on the part of the manufacturers, you know we know
they want their trials to be seen as successful positive trials, and investigators
and sponsors, whether they're pharmaceutical companies or you know in many
cases the government want that, want that as well, its good publicity,
and of course its good business for the pharmaceutical companies."
Dr. Barry: "I don't think taking cynical views really is
going to progress medical practice. What we were looking at is what is
the best way to provide the most benefit to the most nations for the longest
period of time, that's how we acted, I'm proud of it and I think we did
it ethically, I think we did it right, and I think hundreds of thousands,
maybe millions of patients have benefited because of that approach."
Reporter: "And so has your company."
Dr. Barry: "Its no longer my company."
Reporter: "And so has the company you then worked for."
Dr. Barry: "Yes, the company did, but we had many other
drugs, I mean this was not our most prominent drug."
But AZT was Wellcome's second biggest selling drug. After the publicity
for trial 019 shares boomed as a potential global market seemed within
reach up to an estimated ten million people living with HIV. The company
began to promote early use of AZT - one of its handouts said, this could
bring tremendous benefits and have dramatic effects.
Dr. Donald Abrams: "I interpreted that drama and tremendous
in a different way and saw that really we were preventing four out of every
hundred people from progressing and I didn't feel that that was really
worth the potential toxicities and costs."
Reporter: "So what did you make of those adjectives?"
Dr. Abrams: "Well I thought they might have been slightly
But how did Wellcome present AZT's already known side effects? A company
hand out to patients said that the most common side effects, nausea, affected
only a very small minority. But Wellcome's technical manual showed that
in study 019 this very small minority was in fact 22 or 27% depending on
dose. We wanted to ask Wellcome's then Chief Executive John Robb to answer
these doubts about the company's promotion of AZT. He declined to be interviewed
for this programme.
As sales of AZT grew in the early 90s so did public protests by AIDS
activists fearing the drug had hidden dangers. The American trails of AZT
left unresolved its long term risks and benefits. But the study designed
to run for many years was already under way. But not in the United States.
From its base in Oxford a team of British and French doctors had set up
a prolonged trial codename 'Concorde' in 1988. The British side came from
the specialist AIDS team of the Medical Research Council. For the first
time they told Panorama the story of their clash with the company over
the trial. They are the team's Chairman, Professor David Warrell. Scientific
Secretary Dr. Tim Peto, and the principal investigator of the Concorde
trail, Professor Ian Weller.
In 1989 they had to assess the value of the highly publicised results
of trial 019 in America, and what they found left them unconvinced.
Prof. Ian Weller: "What we were looking at was a very small
effect in terms of delay of progression of disease produced by AZT, very
small. And the study, the average follow up or length of treatment was
only just over a year, and we know that 50% of people remain well for ten
years, so just over a year is rather a short time in the life of somebody
who's well with HIV. So the real question for me was, does this degree
of benefits persist?"
Like most studies the Concorde trial depended on the company for free
supplies of the drug. In return two Wellcome scientists joined the Concorde
team. But there was a basic difference over what should count as proof
of the drug's effectiveness. The Medical Research Council wanted to concentrate
on prolonging life or health.
Prof. Weller: "It was important therefore to at least run
a trial for several years to get handle on whether it actually did any
good in the long term in people that were well."
The company in line with some other experts also wanted to rely on a
more immediate measure. AZT's effect on patients' blood. In particular
their number of CD4 blood cells thought vital to the strength of the immune
system. The study's British Chairman rejected this, believing AZT might
artificially raise this blood count, without bringing any real health benefit.
Prof. David Warrell: "We were worried that the CD4 count
might be a cosmetic measure."
Reporter: "Why then would the company want to include a
Prof. Warrell: "Well a CD4 count had the great advantage
that the changes were seen early on. Clearly the longer the study the more
expensive, the more delayed the results."
But only a long term expensive study could settle the question troubling
patients with no symptoms like Pascal De Bock. He started AZT in 1990 as
soon as he found he was HIV positive.
Pascal the Bock: "The doctor who saw me I asked him is there
any treatment, and he told me yes we have got this treatment, we still
don't know exactly what it does but this is the only thing and I was desperate
to sort of cling on to anything that would bring me life or that would
somehow sustain my life."
But Pascal De Bock needed to know if it was worth going on with the
drug when he developed what he fears were side effects.
de Bock: "It became almost like a headache every day, as
soon as I was opening my eyes the headaches were there and they were not
shifted by any type of medication. And that was literally me going up to
bed and going to sleep with a headache and as soon as I was opening my
eyes in the morning the headache was still there."
Reporter: "And how long did that go on for?"
de Bock: "Oh it went on for well for two years. And I couldn't
make up my mind whether that drug or that treatment was doing me any good
or any harm."
The Concorde team studied more than 1700 HIV patients at hospitals in
Britain, Ireland and France. Half were given AZT early while they were
still well. The other half got it only if they began to develop AIDS. Because
of the known short term benefits of the drug, the study had been designed
not to stop early. Only after more than four years were the Concorde team
able to meet by the River Thames in Runnymede to hear the first news of
their results. It was the longest and by far the most comprehensive trial
of AZT. The French team, the British doctors and the company waited eagerly
for the answer to their question - did taking AZT early bring any significant
clinical benefit? They found none long term. Taking the drug before the
onset of symptoms did not produce any significant difference in survival.
Prof. Ian Weller: "We showed no important clinical difference
between the two policies of starting treatment early or later. So the first
thing was one of depression but on the other hand that was a very important
finding. Because we felt that we had shown that the benefit, the early
benefit that had been demonstrated previously wore off.."
In fact it looked worse. The figures showed that more patients died
among those who took AZT early. 96 died taking it early, 76 taking it late.
But the investigators were cautious and anxious to avoid causing alarm.
They calculated that given the size of their samples of patients the difference
in death rates could be due to chance. It was not statistically significant.
Dr. Tim Peto: "We were very concerned indeed to avoid scaremongering
and statistically that 96 is the same as 76 even though mathematically
Reporter: "But in fact the result was the wrong way?"
Dr. Peto: "The result were certainly the wrong way mathematically
There was also a paradox. While it did not improve survival, taking
AZT early did raise the level of patients' CD4 blood cells. So it should
in theory give them longer life. But it didn't.
Prof. David Warrell: "It did seem to be a surrogate marker
of potentially misleading index."
Reporter: "But this was one of the markers which the company
had relied on in its own trial of AZT."
Prof. Warrell: "Exactly, so we felt vindicated in our reserve
or scepticism about what one could infer from the CD4 count alone."
The Concorde doctors had agreed to publish a quick summary of their
initial findings. But as Wellcome still maintained the value of CD4 counts
this led to further disagreement still maintained the value of CD4 counts
this led to further disagreement. The Committee Chairman tried to agree
a form of words with the company to go as a letter in The Lancet.
Prof. Warrell: "The company representatives wanted to tone
down the wording of the letter. As the publication data approached the
telephone communication was more and more frequent and more and more frenzied,
and it really almost degenerated into a matter of considering individual
adjectives. We wanted to say the results casts serious doubt on the value
of using changes in CD4 counts. A serious doubt. The company were very
keen that we should delete 'serious', so we deleted 'serious' under pressure
from the company."
A week after the first Concorde results the letter appeared in The Lancet
in April 1993.
Newsman: "British drug company Wellcome has made millions
selling AZT and today its shares fell over 15 pence or 7% of the company's
AZT came under attack from patients in Britain whose hopes had been
Pascal de Bock: "Initially I took the whole box of my tablets
and put them in the bin and I mean well all the side effects disappeared.
Somehow I wanted to make the wider public know that there was something,
a very darker side into that marvellous treatment to help those people
who suffer so much. Then suddenly the Concorde trial results just appeared
and I felt really ecstatic. It was absolutely marvellous for me to realise
that what the decision that I had made without somehow any medical advice
had been the right one to make."
But the Wellcome Foundation seemed less ecstatic. Four days after the
Concorde results at its London headquarters the company briefed the press
and city analysts like Peter Cartwright about the trial's findings.
Peter Cartwright: "It wasn't the sort of meeting where maybe
its been laid on for months in advance and its well scripted and well rehearsed
and comes across as a very slick and very professional affair. This one
was damage limitation and called at short notice and the company were on
the back foot a little bit."
Reporter: "Why do you call it damage limitation?"
Cartwright: "Well because the share price was falling very
The company told the press that an adequate analysis of Concorde would
show it to fit their own shorter term studies suggesting that early treatment
can improve survival. But this was the exact opposite of what Concorde
had found. One of the company's overhead slides shown to the press contradicted
another Concorde finding, saying survival appears to be correlated with
Prof. Ian Weller: "If anything Concorde showed that there
wasn't a correlation between CD4 and survival, so the whole exercise and
its a personal view, was one of damage limitation."
Reporter: "Was it a distortion of your findings?"
Prof. Weller: "I think you could interpret some of the overheads
as a distortion of the conclusion, the main result, the bottom line of
Prof. David Warrell: "Both the Chairmen of the co-ordinating
committee were outraged by this behaviour of the Wellcome Foundation. I
composed a letter and sent it to the Wellcome protesting the misleading
information provided at the city meeting."
Reporter: "Did you get a response?"
Prof. Warrell: "We didn't."
Panorama wanted to ask Wellcome staff about their comments to analysts
and the press. Dr. Trevor Jones, then Director of Research, and Dr. Paul
Fiddian a member of the Concorde team - they both declined to be interviewed.
Later that year, in December 1993, the whole Concorde team met in a
hotel at Paris Airport to approve the wording of their full report. There
were disagreements on points of scientifical detail, and one overriding
Prof. Weller: "Although there were lots of discussions about
small points and indeed we did accommodate some of the suggestions, trying
to work together on it, the real thing was the last sentence of the paper,
and that was the result of this study do not encourage the early use of
In a compromise with the company this conclusion had been left out of
the first letter in The Lancet. Now Wellcome wanted to delete it from the
full report too.
Prof. Warrell: "Really it was the conclusion, the main conclusion
that they couldn't swallow."
Reporter: "Why couldn't they swallow it?"
Prof. Warrel: "Well why means why scientifically or why
commercially, I mean why commercially because this would decrease the market
of one of their best selling drugs. Why scientifically we could never really
Reporter: "There was deadlock. The Wellcome representatives
continued to insist on deleting this sentence."
Prof. Warrell: "I must say we were a great deal more obstinate
this time than we were over the letter because of our experience of the
letter. There was no certainty at all that had we compromised the company
would not have reneged again after publication."
Prof. Weller: "The company rehearsed its criticisms again
and then late on in the meeting stated that they felt they couldn't endorse
Panorama wanted to ask why, but Dr. Thierry Nebout and Dr. Jane Yeo
the two Wellcome scientists at the meeting have declined to be interviewed.
Prof. Warrell: "What we learned I suppose was, and we shouldn't
have been surprised, is that when the wrong results is produced for a famous
and flourishing company on which a great deal of financial expectation
rests, the company representatives are going to be under a great deal of
pressure, and that the interpretation of those results is going to be stressed,
there's going to be an attempt perhaps to blunt the message, to modify
it, to make amore mellow conclusion from results which seem to be inescapable
in their implications."
Late last year the full five year results of the Concorde study were
announced at the AIDS Conference in Copenhagen. The same team have now
made an independent analysis codenamed 'Opal' of the company trials of
early AZT, and combined the results with Concorde to give greater statistical
Dr. Janet Darbyshire: "We put this together and this was
the purpose of undertaking this joint follow up of the trials you can see
that there is actually no difference between the two policies in terms
Worse, in the combined survival results after more than five years there
are still more deaths among patients taking AZT early. The difference is
still not statistically significant, but the numbers are 411 who took AZT
early, 387 in the group who waited until they began to develop AIDS.
Worse still, in the only fully independent data, the five year Concorde
result taken alone, the difference now is statistically significant. 240
deaths in the early AZT patients, against 199 deaths.
Reporter: "Can you be certain that there is no long term
danger in taking AZT early?"
Dr. Tim Peto: "No we certainly can't say that. There could
easily be a long term danger which the trials aren't large enough to reliably
detect but that certainly is possible."
But alongside this bad news about AZT there was the good news reported
late last year. In a separate trial also run by the Medical Research Council,
and codenamed 'Delta', there were better results if AZT was taken in combination
with other drugs. And about this the company, now merged with Glaxo, was
prepared to take an interview.
Dr. James Palmer: "What it showed was that you could improve
by about 25 to 30%, in other words delay both the onset of AIDS and also
show prolongation of life in patients with HIV, and that was very exciting
because it was a real ray of hope."
And with this second ray of hope in a decade the company again advises
HIV patients to start treatment as early as possible. James Quinlan had
no symptoms of AIDS when he joined the Delta trial in the summer of 1992.
Encouraged by the study's results he's now experimenting with more extensive
cocktails of drugs.
James Quinlan: "The AZT and the 3TC are the antivirals,
and the DDI, and I take hydroxia which is an anti-cancer drug, and the
encyclovir specifically fights herpes, the septrin is an anti-PCP for pneumonia.
They offered me a position on the trial, it was a sort of a white mouse
syndrome and I felt quite happy to be the white mouse. I believed on the
basis of you know if you take the paracetamol the moment you think you're
going to get a headache rather than you know when you've got a blinding
headache and leave it, so I was more convinced on the basis of that I would
quite happily take it earlier even though I didn't have any symptoms."
The Delta results shows patients like James that a cocktail of drugs
is better than AZT alone. But Delta was not designed to answer the vital
question of when to start taking a cocktail. If patients again have their
hopes raised of extra benefit from starting treatment early then its possible
that their hopes may again be dashed by later research. Is there a danger
of going round that whole cycle again?
Dr. Palmer: "The simple answer to that question is yes,
there's always the potential danger, but the answer is at the moment we
don't know. The data that we have with combination therapy suggest that
they have significant benefits over what was available previously, so i.e.
better than no treatment or AZT monotherapy."
Reporter: "But if we don't know why is the company saying
Dr. Palmer: "Well its the typical dilemma that faces physicians
who are treating AIDS patients, and it really is an ethical dilemma because
it would be very hard not to treat a patient with a combination therapy
when you see for instance the results of the Delta study."
Dr. Tim Peto: "We do not know when to start combination
treatment, and se exactly the same issues which we had back in 1987 are
with us today. We don't know whether its worthwhile taking combinations
early when you're still well or whether in fact you can afford to wait
until you're ill."
Patients and their doctors can only know when to start treatment with
an AZT cocktail from another long term study like Concorde. But now it
may prove harder fro researchers to display their independence from the
pharmaceutical industry. There's a squeeze on budgets and the medical research
is now the responsibility of the Department of trade and Industry. In future
more projects will be jointly financed and therefore controlled by drug
companies. Which can only increase the risk that commercial pressures will
compromise scientific enquiry. *