ISIS Report 26/05/06
Actonel: Drug Company Keeps Data from Collaborating Scientists
Prof. Peter Saunders
A fully referenced version
of this article is posted on ISIS members’ website. Details here
Osteoporosis is a serious condition in which the bones become fragile. It affects
about 3 million people in the UK; most common in post-menopausal women, but
younger women and men can be affected as well.
Superficially, bones look inert, but in fact they are constantly “turning over”:
existing bone is broken down and new bone is formed. That’s why it is important
for everyone, not just growing children, to have enough calcium in their diet,
as calcium is a major constituent of bone. If new bone is not being formed as
rapidly as old bone is breaking down, then the bone density will decrease and
the bone will be weaker and more likely to break.
The threshold effect
There are a number of drugs that can be used to help maintain bone density,
and among the most common are a group called bisphosphonates. Proctor &
Gamble (P&G) sells one called Actonel (generic name risedondrate) and its
main rival is Novartis’ Fosamax (generic name alendronate).
Of the two, Fosamax is generally understood to be the more effective at reducing
turnover and increasing bone density. Despite this, P&G hoped to be able
to show that their drug was still as effective as Fosamax at reducing the risk
of fractures, which is what matters. The risk of breaking a bone depends on
a number of factors, not just the rate of calcium turnover, and it might well
be that beyond a certain point, reducing turnover has no effect.
So P&G embarked on a large clinical trial, collaborating with researchers
at Sheffield University in the UK. The results were published in a leading
peer reviewed journal in the field . The authors claim that there is indeed
a threshold, and they provide graphs that appear to show this. They conclude
that there is a level of bone turnover reduction beyond which no further fracture
benefit is observed, just as P&G had hoped.
There isn’t enough information in the paper for one to repeat the calculation
and construct the graphs, but then you wouldn’t necessarily expect there to
be. However, when the lead author, Professor Richard Eastell of Sheffield University,
presented the data at a meeting of the International Osteoporosis Foundation
in 2002, an American investigator did ask how Eastell had arrived at his conclusion
and was surprised to be told that he did not know, as all the analysis of the
data had been carried out by P&G’s statistician.
According to the report in the Times Higher Educational Supplement (THES),
Professor Eastell then suggested that in future the Sheffield group should carry
out the analyses in parallel with P&G. P&G refused, on the curious grounds
that while it “might add an extra layer of credibility,” it would also mean
that “industry loses the opportunity to demonstrate its ability to be a true
partner in scientific endeavours.” P&G also told the THES that it was standard
industry practice to limit access to raw drug trial data .
Is there really a threshold?
That might have ended the matter, but the Sheffield group had already contracted
with P&G to carry out a further study with Dr Aubrey Blumsohn taking the
lead. When the measurements had been completed, Bluhmsohn began to feel uncomfortable
because without the raw data he had no intuition for what was going on. (These
were Phase 3 trials (see Box 1) and so were double blind. This means that the
people carrying out the investigation could not know the results unless they
were given the key, which P&G held.) Eastell asked P&G to allow Blumsohn
access to the data, but this was refused. Despite this, three abstracts were
prepared by P&G with Blumsohn listed as lead author.
Eventually, Blumsohn was allowed to visit the P&G laboratories to discuss
the data. When he saw them, he began to have serious doubts about the conclusions.
He complained that about 40 per cent of the data set was not displayed on the
graphs, and he said that he was now not at all convinced that there really was
a threshold, as the paper claimed.
Out in the open
Blumsohn and P&G were unable to come to an agreement on a way forward.
Eventually he raised his concerns with Sheffield University. Dissatisfied with
the university’s response, he then went to the Times Higher Educational Supplement,
which has since published several articles on the affair . The University
has responded by instituting disciplinary proceedings against him for not following
its internal procedures.
It is not obvious why Blumsohn should have gone through the internal procedures
of the university, because the issue concerns an outside body. He himself says
that he approached the university in the first place only to find out if it
would support him if he were to challenge P&G.
Besides, universities in general are not known for standing up to pressure
from companies that have a lot of money to spend. Think of the long struggle
that Nancy Olivieri had to keep her job at the University of Toronto when her
research proved embarrassing for Apotex, the manufacturer of the drug she was
Since the reports appeared in the media, things have started to happen. P&G
has issued what they call a “bill of rights” for researchers [5, 6]. Its academic
collaborators will now have access to all the data relevant to their work with
P&G, they will have final authority over all publication content, and company
sponsored ghostwriters will provide help with writing papers “only if requested.”
That’s clearly a step forward, but it should have been standard practice all
along, not something that had to be dragged out of P&G by pressure from
the media. We also do not know how the bill of rights will work in practice.
Blumsohn’s lawyers say that P&G is still withholding critical data from
his study. For their part, P&G claim there is no connection between Blumsohn’s
allegations and their new bill of rights .
What does it tell us about the drugs already on the market?
In the meantime, think what all this tells us about drugs that are already
on the market. If P&G’s behaviour was typical of the pharmaceutical industry,
and they insist that it was, there must be many papers reporting the results
of clinical trials that have appeared in peer reviewed journals and purport
to be collaborations between industry and universities, often with the academics
as lead authors (and therefore, presumably, as lead investigators) in which
the academics have never even seen the raw data, still less been allowed to
analyse it. The papers were written by ghost writers, hired by the company,
who were not involved in the research and who are not listed as authors.
How confident can we now be that the drugs are as effective as the manufacturers