Marketing medicines through randomised controlled trials: the case of interferon

British Medical Journal, Oct 31, 1998 by Toine Pieters

"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 trials--even the most sophisticated randomised controlled trials--are 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.

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 enhancers--helping to increasing the host's own response against the tumour--in 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 immunotherapy--one that was going to have an important role in future cancer practices--the 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 drug--Burroughs Wellcome and, most notably, Hoffmann-La Roche and Schering-Plough--apparently 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 budgets--more than $40m each--to interferon (interviews with L Gauci (Hoffmann-La Roche), 18 June 1990 in Basle, and with N Finter, 25 May 1990 in Beckenham, Kent; Powledge[5]).

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 interferon--a pharmacologically active compound--to 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 shovel 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.