How clean was the KLEAN trial? - The Lancet

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Aug 5, 2018 - a single patient in my practice. It has diverted resources from clinical trials that could answer important questions. Imagine if the resources.
Correspondence

TeGenero made considerable efforts to understand details of the structurefunction relation of TGN1412. Finally, Kenter and Cohen state that “In the investigator’s brochure, little guidance is given to doctors on how side-effects can be controlled and treated”. However, the unlikely possibility of TGN1412 eliciting a cytokine storm in human beings was mentioned in section 5.2.2.3 of the document, and the advice provided by TeGenero was approved by the German and British regulatory authorities who considered the application to do the TGN1412-HV trial. I am the Chief Scientific Officer of TeGenero, the sponsor of the TGN1412-HV trial.

Thomas Hanke [email protected] TeGenero, Friedrich-Bergius-Ring 15, D-97076 Würzburg, Germany 1

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Kenter MJH, Cohen AF. Establishing risk of human experimentation with drugs: lessons from TGN1412. Lancet 2006; 368: 1387–91. TeGenero Immunotherapeutics Investigator’s brochure: TGN1412—humanized agonistic anti-CD28 monoclonal antibody, edn 1.1 2005-12-19. Würzburg: TeGenero AG, 2005. http://www.circare.org/foia5/tgn1412investi gatorbrochure.pdf (accessed Oct 18, 2006). Presta LG, Namenuk AK. Non-human primate Fc receptors and methods of use. In USPTO patent full-text and image database San Francisco: Genentech, 2005. Legrand N, Cupedo T, van Lent AU, et al. Transient accumulation of human mature thymocytes and regulatory T cells with CD28 superagonist in “human immune system” Rag2(-/-)gammaC(-/-) mice. Blood 2006; 108: 238–45. Kapadia D, Fong L. CTLA-4 blockade: autoimmunity as treatment. J Clin Oncol 2005; 23: 8926–28.

Authors’ reply Thomas Hanke has given some details about the research that was done with TGN1412. We have never implied that the preclinical work by the TeGenero scientists was not of high quality, and the thoroughness of Hanke’s letter underscores this. However he does miss the point we were trying to make. Our analysis based on the available data at the time of regulatory assessment gives rise to questions. Hanke now gives some of the answers, which are only partly satisfactory, but the details 1570

of this go beyond this correspondence section. We hope that, in future, an exchange like this takes place before high-risk compounds are given to human beings, and not afterwards. We also note that even at this stage there are still important data unavailable for public scrutiny, such as the in-vitro stimulation tests with human and monkey peripheral-blood mononuclear cells. This is regrettable. Also, sponsors and scientists remain responsible for their clinical trials and this cannot be devolved to regulatory authorities, as Hanke seems to suggest. Our paper was not intended to attribute blame but rather to suggest clear communication between all involved in assessing the risks of experiments in human beings to prevent similar events in the future. Hanke’s letter emphasises the necessity of this. MK is executive director and AFC is vice-chairman of the Central Committee on Research Involving Human Subjects, The Hague, Netherlands, which is also the competent authority for drug trials in Netherlands. AFC is director of the Centre for Human Drug Research, which is involved in phase I trials with healthy volunteers.

*A F Cohen, M Kenter [email protected] Centre for Human Drug Research, Zernikedreef 10, 2333 CL Leiden, Netherlands

How clean was the KLEAN trial? Joseph Eron and colleagues’ KLEAN trial (Aug 5, p 476)1 trumpets the finding that GlaxoSmithKline’s (GSK’s) drug fosamprenavir when boosted with ritonavir is noninferior to Abbot’s ritonavir/lopinavir formulation for initial treatment of HIV infection. In my opinion, the KLEAN trial diverted precious research resources to meet the marketing needs of its sponsor, GSK, but not the clinical needs of patients. KLEAN’s results were easily predictable in advance. Similar studies, including the SOLO trial,2

had already been done on boosted fosamprenavir and the results were in line with similar previous studies with ritonavir/lopinavir. I believe that KLEAN’s head-to-head comparison of these drugs would be entirely expected to be in line with previously reported studies. Moreover, and not mentioned by Eron and colleagues, is that boosted fosamprenavir is about US$5000 more expensive per patient per year than ritonavir/lopinavir. As a clinician, I therefore doubt that the KLEAN study will help me to help a single patient in my practice. It has diverted resources from clinical trials that could answer important questions. Imagine if the resources required to conduct KLEAN were put to better use. Imagine if the extra money spent on a non-inferior treatment was spent on something better. Investigators, especially those like Eron who sit on the Optimization of Antiretroviral Therapy Committee of the Adult AIDS Clinical Trials Group (AACTG) should focus on research that has a payoff for patients, not on a drug company’s bottom line. According to Eron’s disclosures,1 he receives honoraria, research grants, and consulting money from GSK. Pharmaceutical companies exert a powerful influence over clinical research and practice by establishing close working relationships with key opinion leaders who serve on government panels such as the AACTG. This facilitates drug companies getting their drugs tested and gains them access to the AACTG’s most precious resource, its patients. Is the current arrangement between industry and academia meeting the needs of clinical research and practice? Do the extensive disclosures of potential conflicts of interest at the end of the KLEAN study provide transparency and ensure accountability? I hope this letter stimulates much needed discussion and debate. I declare that I have no conflict of interest.

www.thelancet.com Vol 368 November 4, 2006