Debate in Lancet about setting up a phase II trial on Ukrain in England

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This is a summary of three letters on Ukrain published in 2000-2001 between the inventor of Ukrain, Dr. W. Nowicky, and Dr David Farrugia and Maurice L Slevin from the from the UK.
Lancet Oncol. 2000 Dec;1:204-5.
Comment in:
Lancet Oncol. 2001 Jan;2(1):10.
Comment on:
Lancet Oncol. 2000 Sep;1(1):54-9.

First Letter:
It started as an appeal from professor Edzard Ernst about "a more constructive approach towards nonconventional alternative treatments, involving a sober assessment of evidence".

In response to this, Dr Farrugia and Dr. Slevin approached the Dr. Nowicky, who "initially responded with interest and enthusiasm, to set up a confirmatorystudy in a group of patients with eight solid tumour types, including 15 patients in each group of lung, breast, gastrointestinal, ovary, mesothelioma prostate, melanoma, and unknown primary.
We proposed a phase II type study, using the dose that had been quoted in several publications as being effective and safe. We planned to recruit 15 patients with measurable disease on computed tomography in each tumour type, so that we would be able to detect a response rate of at least 15%. We might then extend recruitment in the tumour types for which activity was seen. The company initially pledged to support this trial by supplying the drug free of charge, and we agreed to fund the rest of the costs of the study within the medical oncology department at St Bartholomew's Hospital, London, UK. However, after the protocol was approved by our local ethics committee, the company asked for the study to be changed to a phase I dose-finding study in pancreatic cancer, saying that such a study was necessary to investigate efficacy in this tumour type, and that Ukrain had separate dose-dependent modes of action, with lower doses stimulating the immune system and higher doses having a direct apoptotic effect on tumour cells. We argued that this was not the best way forward because the study was self funded, and we first wanted to investigate the claimed efficacy in the tumour types reported in the previous studies, at the same dose. Also, for an agent that has little or no toxicity, the issue of maximum tolerated dose is less important. We believed that a phase II study in 120 patients covering eight tumour types, carried out in a major teaching hospital, at the recommended dose, would establish whether there was any suggestion of activity. "

"The manufacturers of nonconventional treatments complain that the playing field is not level, and that research into these therapies is under-supported. However, our own experience leads us to think that manufacturers are unable, or unwilling, to take advantage of “a sober assessment” when this is offered. We spent substantial time and effort reviewing the literature, formulating a study protocol, and submitting it for ethical approval, only to have the manufacturer withdraw for no plausible reason. As more patients turn to nonconventional treatments, we have an increasing obligation to test claims for their efficacy formally, by standard research practices. We can only do this if the manufacturers of these treatments are prepared to expose them to the rigors of scientific assessment. "

Dr Nowicky then responded:
"Some remarks in the letter about Ukrain in The Lancet Oncology (Dec 2000) by Farrugia and Slevin1 are based upon a misunderstanding, especially
the assertion that we, as the producers of Ukrain, are “unable or unwilling” to take the opportunity for “a sober assessment” of the drug. We agreed immediately to the proposal for a clinical study at St Bartholomew’s Hospital and agreed to supply the drug free of charge. However, we assumed that a clinical study at a major European teaching hospital would be carried out according to Good Clinical Practice (GCP) with independent monitoring, which is a requirement of GCP. Our previous experience has shown that studies which are not carried out according to GCP are not recognised in Europe.
Most of the clinical studies carried out on Ukrain so far have taken place outside the European Union and while investigators have followed the guidelines of GCP the studies have been criticised because not all the formalities were observed. Seen from this point of view, a new clinical study would be of value only if carried out in accordance with GCP. Both the hospital and our company would otherwise bear high costs for a study which would not be recognised. We were therefore unable to understand why Farrugia and Slevin were unwilling to carry out the study according to GCP with independent
monitoring, a precondition which we took for granted would be met at a major European teaching hospital. This is the real reason why the study has not
been set up. We would like to emphasise that we are most willing for an objective, independently monitored study in accordance with GCP to be carried out on Ukrain, that we are prepared to supply the drug free of charge for such a study and that we hope that the study proposed by Farrugia and Slevin can in fact take place."

Dr Farruga and Slevin then replied:
The proposed study, which we outlined in our letter, was in keeping with standard practice for phase II studies and had the approval of our institution’s Ethics committee. The issue of an independent monitoring committee was never raised by Nowicky and we would have no objection to this, if the company would bear the cost, although it is not a routine part of phase II studies. It was the need for an objective
assessment of this compound (which as he rightly says, is lacking in all the clinical papers reported by Nowicky and his colleagues), which prompted
us to suggest this study. We intended to subject Ukrain to the same assessment that any other anti-cancer agent would receive within the context of a phase II study. If Ukrain showed objective evidence of activity there would be no difficulty obtaining pharmaceutical funds for further studies to the level of GCP. Clearly this level of monitoring is outside that which is affordable by a single hospital funded study. It seems to us that the issue of GCP is a red herring designed to prevent the study taking place and it remains unclear to us why Nowicky decided to withdraw his support".