eLetters

138 e-Letters

  • The first serious signal was in 1982

    The first report on 9 cases à of a specific malformation (spinabifida) appeared in the Lancet on October 23, 1982. I signed this letter (E.Robert) that indicated a risk ratio of 30 for mothers taking valproate. Following this alarm, hundreds of publications confirmed the risk, and others (other malformations, and autism know from 2000). A correct warning was given to women in childbearing age in 2015 in France, after the first lawsuits were initiated.

  • Cochrane fails to respond

    I also submitted a criticism online about the review. While I have had email assurances from David Tovey that my contribution would be considered I have yet to hear anything at all.

  • Cochrane: More transparency deficits

    Dear Sir or Madam

    With interest I read your letter concerning the Cochrane HPV vaccines review. However the result for all high-risk HPV-associated CIN 2+ in the “per protocol” analysis of only 16.9% was presented by the German independent drug bulletin arznei-telegramm in September 2008 already (1). At that time the underlying VBPAC background document could be accessed easily on the homepage of the FDA. Currently you can still find it there in the archived content (2).

    The way Cochrane handled your comments are consistent to our experiences: On 25 April 2018 I sent a comment on the updated Cochrane Review "Interventions for emergency contraception", published in Issue 8, 2017 (3). Without presenting any new data the authors had changed their conclusion about the effectiveness of ulipristal acetate (UPA) from “UPA may be more effective than LNG” (= levonorgestrel) in the former version (published 2012) to “UPA was more effective than levonorgestrel” in the actual review. This was based on a new approach to the comparison of UPA versus LNG which was neither discussed nor even mentioned: In the updated review the analysed time elapsed since unprotected intercourse had been extended from 72 hours to 120 hours. There are, however, good reasons to prefer the time window of 72 hours: The risk of pregnancy is significantly lower if LNG is administered within 72 hours of unprotected intercourse than if it is given later than this (3) and in Europe as well...

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  • Defamation: no evidence required

    The article “Drug discovery today: no molecules required” (2018) (by Panchin AY, Khromov-Borisov NN, Dueva EV) questions the imperfections in reviewing scientific publications. The authors use the example of publications on released-active drugs (RA-drugs) as a basis for the paper and their accusations against journal editorial boards. The authors postulate that these drugs do not contain any active ingredients due to the technology used and therefore come to the conclusion that the reviewers and journal editors who have published articles on RA-drugs carried out their work appallingly and made gross mistakes. So the authors state «…the vast amount of flawed publication claiming therapeutic properties and physiological effects of drugs with no active components can highlight the problems of peer-review standards and policies in biomedical journals».
    This particular conclusion is based on approximate theoretical calculations and not on experimental evidence: «If one assumes a 1M initial antibodies concentration (though this is usually not disclosed in release-activity papers) and takes into account Avogadro’s constant (~6.02×10^23 mol^(−1)), then even C12 dilutions are unlikely to contain any antibody molecules». In their article, the authors present these calculations as the main argument to complain to journals. It is noteworthy that in the article the authors do not provide any data or references to any studies conducted by themselves. Neither do the authors provid...

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  • Re: Defamation: no evidence required

    Sergey Tarasov responded to our article “Drug discovery today: no molecules required” with claims of mistakes in our analysis. We are sure that we did not conceal anything of relevance or make any mistakes. This is a response to the claims by Sergey Tarasov.

    1. Tarasov claims that one of us has an undeclared conflict of interest: “However, one of the authors of the article, Khromov-Borisov NN, is a defendant in a defamation lawsuit brought by Materia Medica (June 28, 2018). Materia Medica has sued Khromov-Borisov NN <…> this therefore raises serious doubts over the objectivity and impartiality of one of the authors of the article, who also carried out the data analysis presented in supplementary letter 1”. However, the analysis provided by Khromov-Borisov NN was sent to the editor of International Journal of Diabetes Research on Dec 13, 2017 (Supplementary Letter 1). Then editors of Drug Discovery Today (Feb 5, 2018, Supplementary Letter 5), BMJ (Apr 2, 2018), and BMJ EBM assessed the article including analysis mentioned above. Thus Tarasov presented the chronology completely wrong. First we have submitted our criticism of release-activity (RA) to scientific journals and only then Materia Medica sued one of our co-authors.

    2. We don’t see how any of our previous criticisms of RA drugs and homeopathy creates a conflict of interest or are relevant to the reception of our article.

    3. We have stated that RA drugs contain no active substance. Simple...

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  • Inaccuracies within Lars J Jørgensen's Response to the Cochrane HPV vaccine review. Response to the Cochrane editors Lars J Jørgensen

    I realise there is a lot that has been written on this issue, more than it is possible for someone like me to work through in detail. However, I must point out some factual errors in the Jørgensen et al response dated 17th September.

    I was rather surprised at the level of detail of some of the critique, which even drilled down to cross-checking the exact number of reported deaths in dozens of individual trials. I therefore decided to look at one of the Jørgensen et al claims, and opted for one that I could verify pretty easily, namely the number of deaths in the VIVIANE study.
    https://www.ncbi.nlm.nih.gov/pubmed/27373900

    Jørgensen et al stated that they "found that the Cochrane HPV review gave an incorrect number of deaths for the VIVIANE study (HPV-015): 13 deaths in the HPV vaccine group and 5 deaths in the AlOH3 group; according to VIVIANE’s journal publication (8), there were 14 deaths in the HPV vaccine group and 3 deaths in the Al(OH)3 group."

    A check of their cited reference (8) demonstrates that Jørgensen et al have sourced the 48 week interim 2014 data analysis for this study, rather than sourcing the correct data from the final 84 week data analysis published in 2016, which is quite properly what the Cochrane Review authors sourced.

    The correct citation source states: "Data for serious adverse events related to the vaccine and deaths continued to be collect...

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  • effect sizes

    In general there is often not enough attention paid to the difference of clinical and statistical significance. I do not understand, however, how the authors of the letter conclude that the clinical effect in CASTE-AF was "tiny".
    The application of Cohen's d to a study with a discrete outcome is rather unusual. A more intuitive approach, if one is unfamilar with hazards, would be to use the relative risk as outcome measure. The risk of the primary outcome in the ablated group is 28.5%, the risk in the comparison group is 44.6%. The relative risk is 0.64. The absolute risk reduction is 16% and the number needed to treat is 6.25 (for three years). Not a tiny effect.

  • Problems associated with not using a true placebo in clinical trials

    The problems associated with NOT using a true placebo in clinical trials - in this case GSK's trial for Cervarix - were discussed way back in 2009:

    FOOD AND DRUG ADMINISTRATION CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

    VACCINES AND RELATED BIOLOGICAL PRODUCTS ADVISORY COMMITTEE

    September 9, 2009

    Pg166

    DR. DEBOLD: I just think in the absence of having a true placebo in the entire study, it is very, very difficult to sort out what the effects are here, what is it that we are really dealing with, what is the baseline, versus what potentially is caused by the so-called controls.

    In this particular study, not only was there two different strengths of Havrix used, there was alum used. In the pooled analysis there were a number of other vaccines used as the control, which makes it scientifically very difficult to sort things out.

  • Cochrane review should be revised due to overlooked trials, toxicity of adjuvant, mortality in mid-adult women and lack of discussion on observational studies with serious healthy-vaccinee effect

    Dear Dr. David Tovey,

    I have read your response [1,2] to the paper by Jøorgensen et al. published in BMJ Evidence-Based Medicine [3] relating to the recently published Cochrane Review on HPV vaccines [4], and would like to give my feedback on this issue.
    The key findings of your investigations are as follows:

    1. The Cochrane Review did not miss "nearly half of the eligible trials". A small number of studies were missed due to the primary focus on peer-reviewed reports in scientific journals, but addition of these data makes little or no difference to the results of the review for the main outcomes;
    2. The trials comparators were unambiguously, transparently, and accurately described;
    3. The selection of outcomes for benefits was appropriate and was consistent with World Health
    Organization guidance;
    4. The review included published and unpublished data on serious harms, and the findings on
    mortality were reported transparently and responsibly;
    5. The review was compliant with Cochrane’s current conflict of interest policy;
    6. Cochrane’s media coverage was cautious and balanced, but we recognize that there could be
    improvements in relation to transparency where external experts are quoted;
    7. The BMJ Evidence-Based Medicine article substantially overstated its criticisms.

    I would like to comment on your findings 1, 2, 4 and lastly, I added comments as 8. Most observational studies neg...

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  • Strongly support the conclusions of this article written by Jørgensen et al.

    The authors addressed important limitations in the Cochrane HPV vaccine review and stated that the Cochrane HPV vaccine review authors should make every effort to identify all trials and the trials' limitations in their conclusion. We (members of Medwatcher Japan [YAKUGAI Ombusperson], an NGO that was launched in 1997 to monitor and prevent drug-induced disasters) strongly support their conclusions.
    Medwatcher Japan released an open letter (original Japanese document) ‘Critical Opinion on Cochrane Review of HPV Vaccines’ dated on June 8th, 2018 and raised some comments concerning the content of the Cochrane HPV vaccine review and the governance of the Cochrane organisation. We have submitted the open letter (English translation of the original Japanese document) to some relevant parties in charge of Cochrane on August 13th, 2018. Furthermore, we have submitted the short version which was limited to the specifics of the contents of the Cochrane HPV vaccine review via the feedback system on The Cochrane Library on August 31st, 2018. It has been confirmed that the short version was published via the Cochrane Library feedback system. We have not, however, received any responses directly from the Cochrane.
    Therefore, in addition to the points raised in this article by Jørgensen et al., we would like to address the following key comments concerning the content of the Cochrane review in this response:

    1. Since the effectiveness claimed in the Cochrane revi...

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