Fwd: Fwd: marketing medicines through RCT's

["A Pieters" <A.Pieters.medhistory@med.vu.nl>]

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To:	SMTP[love@cptech.org]
From:	A Pieters@Metamedica@preklin
Date:	Tue Dec 22 03:00:02 1998
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To:	SMTP[listproc@essential.org]
From:	A Pieters@Metamedica@preklin
Date:	Tue Dec 22 02:57:57 1998
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I would like to focus attention to the following publication that may be of 
interest to the news list  pharm-policy@essential.org.


BMJ 1998;317:1231-1233 ( 31 October )

Education and debate

Marketing medicines through
randomised controlled trials: the
case of interferon 

Toine Pieters, lecturer.  

Section of Medical History, School of Medicine, Vrije Universiteit
Amsterdam, 1081 BT Amsterdam, Netherlands 

Correspondence to: Dr T Pieters, Israelslaan 8-iv, 3582, HK Utrecht,
Netherlands tpieters@bio.vu.nl 

"When it comes to clinical trials, few issues are simple.
And many are controversial" wrote the Science correspondent Gary Taubes in 
1995.1 Taubes'
dictum seems to be at odds with the public model of the randomised clinical 
trial as a most
helpful tool to relieve medical practice of that most feared element known to 
scientists and
regulators: subjectivity. Are most doctors and regulators who firmly believe 
in the randomised
controlled trial as the key to an "evidence based medicine" mistaken? Given an 
ideal world
without social, professional, and economic interests affecting judgments of 
the efficacy and risks
of medical treatments, one might have answered "no." It is impossible, 
however, to conceive of
such a trial taking place in a human vacuum. Conducting randomised controlled 
trials involves
establishing links and commitments between many different individuals and 
organisations,
including clinicians, laboratory researchers, patients and their families, 
regulators, and drug
companies. In being shaped by the specific context of medical practice, 
clinical trialseven the
most sophisticated randomised controlled trialsare not value-free measuring 
devices that
objectively evaluate the efficacy of new treatments. Like any other medical 
device associated
with our daily lives, randomised controlled trials incorporate the beliefs and 
ideas of the people
who developed them and then are moulded by those implementing the 
methodology.2 I use here
the story of interferon to illustrate the complexities surrounding the 
application of this
supposedly value-free research methodology. Interviews referred to in the 
article were between
myself and the person cited. 

   Summary points 


       Randomised clinical trials are regarded as a most helpful tool to 
relieve medical
       practice of subjectivity 

       Interferon became a part of everyday clinical practice through 
randomised clinical
       trials 

       Despite initial disappointment with its clinical efficacy, interferon 
became
       legitimised as a part of medical practice 

       Randomised clinical trials had the side effect of widening interferon's 
therapeutic
       profile and were central to the marketing strategies of pharmaceutical 
companies 

       The use and interpretation of randomised clinical trials differ 
substantially for
       experimental drugs in serious illness and for research into less 
serious diseases 




  
      Beyond interferon


In the late 1970s, after scientific claims that interferon had an inhibitory 
effect on tumours,
interferon stirred up a global media hype. 3 4 The euphoria surrounding 
interferon as a "miracle
cure" for cancer was short lived and faded when it seemed that interferon's 
performance in large
scale cancer trials had been disappointing and that it often produced side 
effects in patients.5
Given the intense disappointment in the early 1980s in the healing power of 
what later became
dubbed "the miracle drug looking for a disease," how did interferon manage to 
become
legitimised as part of medical practice in the 1990s? 

As might be expected, the people working on interferon tried hard to account 
for the
disappointments to safeguard funding. Interferon researchers conveyed the 
impression that with
more questions than answers they were just beginning to explore the potential 
of the drug. The
diversity of interferons with distinct and complementary activities seemed to 
grow every day,
although clinical testing of the first interferon preparations produced with 
recombinant DNA had
yet to start. The consensus view was that, although interferon as a single 
agent might turn out to
be useful in treating viral infection, it might ultimately prove most valuable 
as part of the
increasingly popular "multitreatment" approach in cancer. Interferons could 
then be used as
biological enhancershelping to increasing the host's own response against the 
tumourin
combination with the three main cancer treatments: surgery, chemotherapy, and 
radiation.6-9 

By creating an image of interferon as a prototype of a promising, new, but 
still poorly
understood area of cancer treatment known as immunotherapyone that was going 
to have an
important role in future cancer practicesthe promoters of interferon 
established a more
permanent base for support. The overall message was, as a science reporter of 
the Washington
Post aptly expressed it in his headline, "Beyond interferon." 10 Cancer 
treatment centres that
aspired to maintain an image of being at the cutting edge of the field of 
clinical oncology could
not afford not to study an experimental treatment that was closely linked with 
the latest
developments in tumour biology and molecular biology (interview with E Borden, 
12 October
1992, Wisconsin). 

In line with government supported research programmes, the pharmaceutical 
industry focused on
interferon as part of a new kind of disease management: immunotherapy within a 
multitreatment
framework. The three "interferon champions" that had most heavily invested in 
the
drugBurroughs Wellcome and, most notably, Hoffmann-La Roche and
Schering-Ploughapparently recognised the strategic and commercial importance 
of taking
advantage of the more general move across medicine towards combination 
treatment. In
1983 Hoffmann-La Roche and Schering-Plough allocated 15% of their research 
budgetsmore
than $40m eachto interferon (interviews with L Gauci (Hoffmann-La Roche), 18 
June 1990 in
Basle, and with N Finter, 25 May 1990 in Beckenham, Kent; Powledge5). 

However, the regulators found the multitreatment approach difficult to assess 
as their evaluative
practice and standards were still governed by a single agent, therapeutic 
philosophy. For
interferona pharmacologically active compoundto be considered legally as a new
therapeutic drug, it had to be officially evaluated as a single agent. This 
implied that before
licensing procedures could be taken into consideration, the companies had to 
look for a disease,
rare though it might be, that justified a need for interferon (interviews with 
J Petriccianni,
6 November 1992, Cambridge, MA, and with L Gauci, 18 June 1990). As most 
trials showed
that interferon alone compared unfavourably with drugs already available, the 
interferon
industry faced the seemingly Herculean task of establishing an unambiguous 
justification for
clinical use. 

  
      Promoting use of interferon


In search of suitable diseases as candidates for interferon as a treatment, 
the drug companies
actively supported randomised controlled trials to evaluate the effects of the 
drug on as wide a
variety of diseases as possible. They offered clinical investigators 
worldwidefree of
chargelarge quantities of their interferon products to perform randomised 
controlled trials.
Interferons were tested against hepatitis B, lymphomas, colds, breast cancer, 
prostatic cancer,
multiple sclerosis, herpes keratitis, malaria, AIDS, and many other diseases 
related to cancer
and viruses. The drug companies mounted one of the most intensive clinical 
trial programmes
ever set up to evaluate a new pharmaceutical agent.11-14 

Once the indication for hairy cell leukaemia was officially established in 
1986, the marketing
branches of the drug companies worked hard to create a need for interferon 
(interview with T
Pike (Roche), 22 June 1990, Basle). The drug industry was well aware that it 
was highly
dependent on the cooperation of clinicians both to define additional clinical 
situations in which
the interferons might be applied and to help market the multitreatment 
concept. Highlighting
success instead of failure in research publications sponsored by 
industrywithout denying
current limitationscame to form the implicit justification for the further 
growth of the clinical
trial "enterprise." 15-18 The impression conveyed was that participating 
clinicians would stand
out as pioneers of a new era of treatment (in 1983 the drug company Schering 
made available a
series of three films (Interferon in Prospect) to clinical investigators 
worldwide). 

Optimising response rates seemed to be the explicit aim of virtually any 
clinical research
project dealing with interferon.19-21 Clinical researchers who participated in 
testing interferons
claimed response rates of 10-50% except for hairy cell leukaemia (response 
rate higher than
80%). The problem and advantage of using percentages was that success seemed 
to be a highly
ambiguous term. Overall response rates ("efficacy") resulting from clinical 
studies under
controlled circumstances might look promising, even when it remained unclear 
what this
actually meant for individual chances of success and how well a treatment 
might perform in
everyday clinical practice ("effectiveness"). Regardless of interpretation, 
however, response
rates remained low in most diseases, suggesting that it could help only some 
of the patients some
of the time. 

                      Under normal disease conditions this kind of negative 
scientific
                      assessment would dissuade doctors from applying a 
therapeutic
                      drug. But in circumstances where there is no hope for a 
cure, the
                      rules of the game are different for both doctors and 
patients. In
                      diseases in which successful treatment is rare, seeking 
treatment
                      through medical intervention is a gamble which can have 
few
                      winners. Gambling is an alluring analogy for all parties 
as it turns
                      poor clinical results into acceptable chances, allotting 
responsibility
for failure to bad luck rather than medical or other capacities. 

With the relentless support of the drug industry and patients in desperate 
need of a cure, and
through scientific drive and professional ambition, clinicians continued to 
tinker with the design
of trials. They tried different combinations and different routes and 
durations of
administration.20-22 In doing so, they ultimately tinkered towards success in 
terms of
establishing new therapeutic drug practices for interferon and actively 
working on the
treatment's effectiveness. Although superior treatments for the treatment of 
hairy cell leukaemia
became availableand have largely replaced the use of interferon for this 
conditioninterferon
as an adjunct to other treatments became part of the routine treatments of a 
growing number of
diseases. 

In positioning interferon as a "helpful neighbour," compatible with and 
supportive of existing
treatment practices, the pharmaceutical companies succeeded in having 
interferon relatively
quickly absorbed into the medical infrastructure, requiring increasingly large 
amounts of money
for its use. As a consequence, opposition to interferon currently revolves 
less around questions
of need than around questions of cost or economic feasibility, which 
increasingly dominate the
political agenda of "marketplace" medicine. 

  
      Organising marketing strategies around randomised
    controlled trials


The story of how interferon managed to become part of the "doctor's bag" 
clearly shows how the
conduct, organisation, and evaluation of randomised controlled trials, and 
what they are capable
of, is dependent on the specific context of use. The interferon case provides 
a warning example
to those who uncritically promote randomised controlled trials as the badge of 
rational
medicine. In achieving a key position in the distribution of research 
resources and materials
needed to set up such trials, the pharmaceutical industry increasingly 
dictated development and
clinical use of interferon. It was the industry itself that profited most from 
the very dialectical
nature of the "enterprise" of the randomised controlled trial. I have shown 
that the randomised
controlled trials proved effective not only in evaluating the safety and 
benefit of interferon as a
therapeutic drug but also in the marketing of the commercially interesting 
multitreatment concept
that turned the interferons from unwanted drugs into top selling 
pharmaceuticals. 

  
      Acknowledgments


Funding: None. 

Competing interests: None declared. 

  
      References


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1995; 267:
    25[Medline].
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scenes. Medical History
    1993; 37: 270-295[Medline].
  4.Pieters T. History of the development of the interferons: from test-tube 
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London: Chapman
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(Accepted 6 October 1998) 

© British Medical Journal 1998 

This article has been cited by other
articles: 

    Chalmers, I. (1998). Unbiased, relevant, and
    reliable assessments in health care. BMJ 317:
    1167-1168 [Full text]