Tuesday, 18.05.2021

Pierre Baumann and Francois Ferrero: An official inquiry of the clinical research activities (1946-1972) of Roland Kuhn (1912-2005) 

 

Walter Brown’s comment

 

       Pierre Baumann and François Ferrero note in their summary of the official inquiry’s report into the clinical research activities of Roland Kuhn that in 2013 articles began to appear in Swiss newspapers reporting  that in the 1970s and earlier patients at  the Psychiatric Hospital in Münsterlingen were subjected to poor medical conditions, inadequate treatment and,  in particular, the use of experimental treatments without their knowledge or consent. 

       In 2015 the Canton of Thurgau, Switzerland, where the hospital is located, set up a commission to investigate patient care at the Psychiatric Hospital  and in particular the research activities carried out there by Roland Kuhn.  The interdisciplinary commission comprised  a research team of five historians, an eight member advisory board consisting of legal experts, pharmacologists and doctors, and a raft of consultants including historians, scientists and ethicists. They dug through hospital records, drug company archives, the archives of the federal drug administration and Roland Kuhn’s personal papers. The investigation went on for  three and a half years and cost about $1 million. Their report came out in September 2019 in the form of a 336-page book titled Testfall Munsterlingen, Klinische Versuche in der Psychiatrie, 1940-1980 (Test Case Munsterlingen, Clinical Trials in Psychiatry 1940-1980) (Meier, König and Tornay 2019).

       This report is, on several grounds, a very important one. As Baumann and Ferrero point out, “It is urgent that the international scientific and medical community is rapidly informed about the research carried out by Roland Kuhn between 1940 and 1980 in Münsterlingen.” The book and its summary are in German, not yet translated into English.  Pierre Bauman and François Ferrero provide here a brief description of some of the findings and in doing so have done our field an important service. An informed take on the investigation, however,  requires perusal of the entire report.  Still, even this admittedly partial sketch of the investigation raises enough  concerns about Kuhn’s research approach to warrant thorough scrutiny of the full report.

       Roland Kuhn is an iconic figure in the history of psychopharmacology. He is credited with the discovery of imipramine, the first tricyclic antidepressant and among the few first generation psychotropic drugs still in use. Further, Kuhn identified the type of depression (endogenous) most likely to benefit from imipramine (and, it turns out, other antidepressants). And, not hesitating to provoke the research establishment, Kuhn insisted that his “method” of drug discovery, open ended, frequent and meticulous clinical observation, was far superior to the elaborate and systematic research methods - rating scales, placebo controls, statistical analyses - coming into play when he was doing his imipramine research. No one is about to abandon the RCT and its methodological niceties on Kuhn’s say so; but, as Ned Shorter and others suggest,  Kuhn’s clinical observation approach to drug discovery might usefully inform current fashions in drug discovery, which more often than not come up empty handed.

       So Kuhn made solid, albeit in some spots idiosyncratic, contributions to psychopharmacology. It’s no secret though that as both a researcher and a person he got mixed reviews. He was widely respected and recognized for his imipramine discovery and he received several honorary degrees.  He also stirred up a good deal of animosity in part owing to his insistence on claiming all the credit - some think unfairly - for the imipramine discovery.

       Kuhn  was dignified, scholarly and, according to some, attentive to and concerned about his patients and an astute conscientious clinician.  He was also arrogant, contentious and angry about the snubs of his colleagues. And he was snubbed. On more than one occasion Kuhn was not invited to psychiatric conferences focused on antidepressants, a perplexing omission given his status as a pioneer in the field.

       In a 1996 interview (Healy 1998), Kuhn complained that many people wrongly maintained that his discovery of imipramine’s antidepressant activity was an accident, that luck or serendipity was involved. He claimed that Jean Thuillier, a prominent French psychopharmacology researcher,  in recounting the history of antidepressants said:  “Un petit psychiatrie de champagne, foutu dans ses montagnes, a fait par hazard le decouverte de Tofranil” (“An insignificant, provincial psychiatrist, lost in his mountains, discovered Tofranil by chance”). Kuhn vociferously disputed the idea that his discovery was any sort of  accident. And Thullier claimed that it wasn’t him but someone else who referred to Kuhn this way. And so it went.

       Now to the portrait of a complex, clearly imperfect but indisputably accomplished man we must add another feature. The report of the Münsterlingen investigation leaves no doubt that Kuhn carried out his drug studies without the consent or knowledge of the patient participants. In some instances he went to considerable length to deceive patients about the nature of their treatment.

       As Ned Shorter, Max Fink and Don Klein point out, in the 1950s, when Kuhn did his imipramine research the subject protection ideas and regulations of today were not part of the research culture. It would be unreasonable to judge Kuhn by today’s standards.  But in 1964 the Declaration of Helsinki was introduced  setting  out the ethical principles of research, including the importance of informed consent. Those principles were widely adopted and provided the basis for the subject protection regulations now in place. In 1970 the Swiss regulatory authority adopted and implemented them. Kuhn, though, continued to conduct his research at Münsterlingen without patient consent until he retired in 1980 and he continued to conduct clinical trials from his private office after that.

       Further, it’s fair to assume that before research subject protections were mandated, investigators differed widely in how they approached patient participants. In trying to make sense of what Kuhn was up to it would be instructive to know how his approach to his research subjects before Helsinki compared to what his contemporaries did.

       I usually agree with everything Ned Shorter says and I share his implied impatience with political correctness and his reluctance to subject Kuhn to a witch hunt.  Still, both Baumann and Ferrero’s  summary and the 2019 press release (in English) from the research  team that also sums up the report’s findings (Meier 2020),  leave no doubt that Kuhn disregarded his patients’  autonomy and wishes to an extent that is appalling by today’s standards. That he may have acted  in accordance with the research culture of his time, at least before 1964, does not negate the historical value of obtaining a complete picture of his research activities and methods, including his approach to his research subjects.

       The point is not to sully Kuhn’s legacy or to “cancel” him, but rather to provide a comprehensive picture of how he went about his work. Our understanding of the drug discovery process would  be enhanced if we could figure out how Kuhn’s paternalistic (to put it mildly) approach to his patient subjects affected his treatment discoveries.  Was his discovery of imipramine’s antidepressant activity, for example,  facilitated by his disregard of consent?

       It is clear from the summaries of the commission report that Kuhn continued to conduct clinical research without patents’ consent, “We have never asked patients for their consent,”  he wrote in 1980. And he persisted in misinforming them about the substances they were getting well beyond the time when informed consent was mandated and widely applied in Switzerland and elsewhere. Nonetheless, although Kuhn certainly operated on the edge of clinical research ethics, and seems to have crossed the boundary in several instances, the extent to which he deviated from the standard practices of the time is not clear. Even in the pre-Helsinki era we can fairly assume that clinical researchers differed in what they told research subjects and in the degree of coercion they applied. It would be good to know where Kuhn stood in this regard among his peers.

       The commission’s full report warrants careful perusal. Disturbing as its revelations may be, they need to see the light of day, they need to be thoroughly evaluated and they need to become part of the historical record.

 

References:

Healy D. The Psychopharmacologists II. London:Altman; 1998.

Meier M, King M, Tornay M. Test case Münsterlingen: clinical trials in psychiatry, 1940-1980. Zurich: Chronos. 2019.

Meier M. English translation of the German Press Release on findings in the official report (Pierre Baumann and Francois Ferrero: An official inquiry of the clinical research activities [1946 -1972] of Roland Kuhn).   inhn.org.controversies. March 26, 2020.

 

February 18, 2021