Reporting harms more transparently in trials of cancer drugsBMJ 2018; 363 doi: https://doi.org/10.1136/bmj.k4383 (Published 01 November 2018) Cite this as: BMJ 2018;363:k4383
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I would like to thank Barton et al. for their comments on our paper. It is unfortunate that they disagree with the CONSORT statement on reporting harms because their statement that "we do not agree that descriptive terms (such as acceptable, manageable, feasible or tolerable) should be eliminated from oncology trial publications" is in clear contradiction to the CONSORT recommendation. We have explained at length in our paper, in the box and in the podcast why the use of such terms downplays toxicities and may incorrectly influence the risk-benefit trade-off decisions for the patient, and I do not wish to reiterate the same here.
The authors of the letter cite treatment discontinuation rates, dose escalation rates, etc., to make a point that the drugs were indeed "acceptable, tolerable or manageable"; however, we cite the percentages of severe, serious and fatal adverse effects. The main point of our paper is that it should be only the patients who decide whether the toxicities are acceptable. Neither we, the authors of the BMJ paper nor the authors of the letter nor the treating physicians can label toxicities that patients experience as acceptable; it's always the patients' call. However, I again firmly disagree that even the drugs that have fatal adverse effects can be considered as having "manageable toxicities" as the authors of the letter point out using the example of liposomal irinotecan. The very fact that some patients died due to side effects from the drug proves that those side effects were not "manageable".
The other point made by the authors of the letter that the top journals wouldn't have allowed these papers to pass through if they were not accurate is a big question on the journals, that probably the journals should introspect. I agree with the final point that the harms shouldn't be considered in isolation. Throughout our paper, we discuss about the risk-benefit trade-offs. Again, all these judgments have to be made by the patients and not anybody else. We have even provided two solutions in our paper about how we can address this issue.
Thank you for the opportunity to clarify our points. I have no conflicts of interest to disclose.
Competing interests: No competing interests
We agree with many of the sentiments expressed by Gyawali et al in their article “Reporting harms more transparently in trials of cancer drugs”. In particular, we agree that the incidence and severity of adverse events should be reported accurately and objectively, using recognised scales such as the NCI CTCAE (a five-point scale in which Grade 5 indicates a fatal outcome). We also agree that many drugs used in oncology have toxicity profiles that would not be acceptable in other medical conditions, that it is important to assess quality of life/patient-reported outcomes in randomised studies, and that only individual patients can decide what is acceptable or tolerable for them.
However, we do not agree that descriptive terms (such as acceptable, manageable, feasible or tolerable) should be eliminated from oncology trial publications. As long as the meaning is clear and substantiated by data, it seems reasonable to use such terms in discussions or when succinctly summarising the overall safety data. Nor do we agree that such descriptive terms automatically imply a down-playing of harms. Furthermore, we feel that analysing individual words or phrases out of context is over-simplistic and potentially misleading.
Using the examples provided by Gyawali et al:
• The full sentence used in the discussion section of the ribociclib study publication is, “Most patients had an acceptable adverse-event profile with long term administration of ribociclib plus letrozole, with 7.5% requiring permanent discontinuation of both ribociclib and letrozole because of similar adverse events and similar percentages because of decisions made by either patients or physicians in the two groups” (1).
The full sentence makes it clear that the adverse event profile was considered acceptable based on rates of physician and/or patient-instigated treatment discontinuation, which were similar in the experimental and control arms. When viewed in context, the phrase, "Most patients had an acceptable adverse-event profile" does not appear to downplay the harms of ribociclib.
• The full sentence used in the discussion section of the tasquinimod study publication is, “The tolerability of tasquinimod was good overall, and the vast majority of patients were able to escalate to the maximum 1-mg/day dose according to the pre-defined schedule” (2).
In this trial, individual patients underwent dose escalation over a 6-week period and, earlier in the paper, the authors indicate that 82% of patients escalated to the target dose (1 mg/day) in the tasquinimod arm versus 92% of patients in the placebo arm. The statement when viewed in its entirety and in context seems to be a reasonable summary of the data and in no way underplaying the harms of tasquinimod.
• The concluding paragraph in the publication of liposomal irinotecan in pancreatic cancer starts with the sentence “In conclusion, the results of this phase 3 study show that nanoliposomal irinotecan in combination with fluorouracil and folinic acid extends survival and improves other efficacy variables in patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based regimens, and has a manageable and mostly reversible safety profile.”
Gyawali et al indicate that this is incompatible with the fact that five treatment-related deaths occurred in the “intervention arm”. However, the study included two intervention arms – nanoliposomal irinotecan monotherapy and nanoliposomal irinotecan plus fluorouracil and folinic acid. Four of the five treatment-related deaths occurred in the nanoliposomal irinotecan monotherapy arm and indeed, toxicity in this treatment arm was considerably greater than in the combination arm and the control arm, consistent with the higher doses of nanoliposomal irinotecan used. The difference in toxicity (based on a range of parameters) and quality of life between the combination arm and the control arm was much smaller and this is described in detail in the publication. Viewed in its entirety and in context, this sentence does not seem to underplay the harms of nanoliposomal irinotecan when given in combination with fluorouracil and folinic acid (the regimen supported by the authors of the NAPOLI trial publication).
Although we give our interpretation of the three examples above, it is pertinent to note that all three papers would have undergone peer review before publication (as would all the papers in the prestigious journals selected for review by Gyawali et al). It is highly unlikely that peer reviewers (undoubtedly including practising oncologists) would have allowed misleading or unsubstantiated claims to be published in these journals.
Finally, the harms of therapeutic agents cannot be viewed in isolation. The condition being treated and the efficacy of the product have a bearing. A patient with cancer might well accept greater side effects from a new therapy if there is the prospect of benefit in terms of progression-free or overall survival.
Competing interests: The views and opinions expressed in this article are those of our own and do not reflect the views or position of any company we are working with. Claire Barton is a freelance pharmaceutical physician/medical advisor with Barton Oncology Ltd, specialising on oncology drug development. She undertakes paid consultancy for pharmaceutical companies and other organisations including (in the last ~2 years) Cancer Research UK Centre for Drug Development, Cancer Targeting Systems Inc, CellCentric Ltd, Certara LP, Innate Pharma SA, Macrophage Pharma Ltd, MorphoSys AG, Orion Clinical Services Ltd, PTEN Research Foundation, Roche Products Ltd, SFL Services GmBH, T3 Pharmaceuticals AG, and the Wellcome Trust Ltd. Claire Barton is on the advisory board for SFL Services GmBH and owns shares in GlaxoSmithKline. Yasser Mostafa-Kamel is a clinical oncologist currently working as a freelance pharmaceutical physician/medical consultant. He is Managing Director of ASYS Pharmaceutical Consultants-APC Inc, specialising on oncology drug development and medical affairs. He is a peer reviewer for the ASCO educational book, an editorial board member for the International Journal of Clinical Oncology and Cancer Research, and a member of the American Society of Clinical Oncology, American Society of Haematology, European Haematology Association, and Canadian Association of Professionals in Regulatory Affairs (CAPRA). He is a previous employee of Eli-Lilly & Company, F. Hoffmann-La Roche, GlaxoSmithKline, and PAREXEL International. Richard Kennedy is Professor of Medical Oncology at Queen’s University of Belfast, UK. He is also Global Vice President and Medical Director of Almac Diagnostics Services, which has supported some of the Pharmaceutical companies responsible for the drugs referenced in the article, although not in these specific trials. Robert Miller is Managing Partner and Chief Medical Officer for Artemida Pharma, a Consultancy which works as an independent organisation for clients and works extensively in the oncology field. Faisal Mehmud is Executive Medical Director for Bristol Myers Squibb UK & Ireland, and previously was employed with Novartis (USA), GlaxoSmithKline (USA), and Sanofi (France & UK), predominantly specialising in oncology drug development and medical affairs. Austin Smith is Medical Director of Theredex Oncology Ltd.
This article makes a number of very important points with which I agree strongly. It is important because the benefits of drugs in cancer are often, but by no means always, of minimal clinical relevance. This is especially the case where effective treatments are lacking. However the argument sometimes heard at regulatory committees when this is pointed out is countered by "we must have something to give these patients". In other words, the drugs are licensed for the benefit of clinicians and not patients.
As the authors imply, it is a pity that reports of trials do not follow CONSORT guidelines on harms.
Incidentally however, Gyawali et al give as a citation to the CONSORT guidelines a reference to a paper by the lead author, which seems to relate to quality of life outcomes rather than harms. Perhaps BMJ editors and reviewers as well as the authors missed this? Surely it would be sensible to cite the CONSORT paper itself? 
1. Ioannidis JPA, Evans SJW, Gotzsche PC, O'Neill RT, Altman DG, Schulz K, et al. Better reporting of harms in randomized trials: An extension of the CONSORT statement. Annals of Internal Medicine. 2004;141(10):781-8.
Competing interests: I am one of the authors of the CONSORT paper
Recently, the work  “Reporting harms more transparently in trials of cancer drugs” was published in The BMJ, which analyzed and summarized the terms on downplaying the seriousness of adverse effects in phase II or III randomized trials from five top journals in 2016. And their results showed harms in the experiment group were more than the control. I agree with them and harms should be reported in detail and transparently. Here some points those would be added.
In order to regulate reporting of harms in randomized trials, a reporting guideline--CONSORT-harms--was published, and it has been cited 1492 times (from Baidu Scholar, Nov 3, 2018). Some questions may have been resolved but according to their results, the current status was not optimistic. A big potential reason was lacking awareness of reporting transparently with complete details of the trials process, which would lower the utility of intervention.
Recently, a study  “The reporting of safety among drug systematic reviews was poor before the implementation of the PRISMA harms checklist” was published in JCE, and showed systematic reviews also reporting poorly. We should note that no matter whether randomized trials or systematic reviews, they are all regarded as great evidence in Evidence-based Medicine, therefore, all of their processes must be complete and transparent from the start for the final goal--improve health, increase utility and decrease waste.
Conflicts of interest
I declare that I have no conflicts of interest.
1. Waleed Alhazzani, Kimberley Lewis, Roman Jaeschke, et al. Conflicts of interest disclosure forms and management in critical care clinical practice guidelines.Intensive Care Med, 2018,
2. Ioannidis J, Evans S, Gotzche P, et al． Better reporting of harms in randomized trials: an extension of the CONSORT statement. Ann Intern Med, 2004, 141(10) :781.
3. Hoffmann T C, Oxman A D, Ioannidis J P, et al. Enhancing the usability of systematic reviews by improving the consideration and description of interventions. Bmj, 2017, 358: j2998.
4. Li L, Xu C, Deng K, et al. The reporting of safety among drug systematic reviews was poor prior to the implementation of the PRISMA harms checklist. Journal of clinical epidemiology, 2018.
Competing interests: No competing interests