Restoring invisible and abandoned trials: a call for people to publish the findings
BMJ 2013; 346 doi: https://doi.org/10.1136/bmj.f2865 (Published 13 June 2013) Cite this as: BMJ 2013;346:f2865
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Dear Editor
May I concur with this 'call to action' and add my small contribution published in the Lancet Infectious Diseases.
The article can be accessed here; https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(16)30546-1/fulltext
Competing interests: My group has received funding from a variety of sources including UK research councils such as the MRC and overseas charities such as the Washington DC based CMSRI to undertake research on the safety of aluminium adjuvants used in vaccines.
We write to issue a call to action to restore the reporting of thirteen trial publications or published follow-up studies in GSK’s clinical development program for bivalent human papillomavirus (HPV) vaccine (Cervarix). These publications are:
NCT00689741 Harper DM, Franco EL, Wheeler C, Ferris DG, Jenkins D, Schuind A, Zahaf T, Innis B, Naud P, De Carvalho NS, Roteli-Martins CM, Teixeira J, Blatter MM, Korn AP, Quint W, Dubin G; GlaxoSmithKline HPV Vaccine Study Group. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. Lancet. 2004 Nov 13-19;364(9447):1757-1765.
NCT00120848 Harper DM, Franco EL, Wheeler CM, Moscicki AB, Romanowski B, Roteli-Martins CM, Jenkins D, Schuind A, Costa Clemens SA, Dubin G; HPV Vaccine Study group. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet. 2006 Apr 15;367(9518):1247-1255.
NCT00294047 Skinner SR, Szarewski A, Romanowski B, Garland SM, Lazcano-Ponce E, Salmerón J, Del Rosario-Raymundo MR, Verheijen RH, Quek SC, da Silva DP, Kitchener H, Fong KL, Bouchard C, Money DM, Ilancheran A, Cruickshank ME, Levin MJ, Chatterjee A, Stapleton JT, Martens M, Quint W, David MP, Meric D, Hardt K, Descamps D, Geeraerts B, Struyf F, Dubin G; VIVIANE Study Group. Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years: 4-year interim follow-up of the phase 3, double-blind, randomised controlled VIVIANE study. Lancet. 2014 Dec 20;384(9961):2213-27.
NCT00586339 Denny L, Hendricks B, Gordon C, Thomas F, Hezareh M, Dobbelaere K, Durand C, Hervé C, Descamps D. Safety and immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine in HIV-positive women in South Africa: a partially-blind randomised placebo-controlled study. Vaccine. 2013 Nov 19;31(48):5745-53. doi: 10.1016/j.vaccine.2013.09.032.
NCT00481767 Sow PS, Watson-Jones D, Kiviat N, Changalucha J, Mbaye KD, Brown J, Bousso K, Kavishe B, Andreasen A, Toure M, Kapiga S, Mayaud P, Hayes R, Lebacq M, Herazeh M, Thomas F, Descamps D. Safety and immunogenicity of human papillomavirus-16/18 AS04-adjuvanted vaccine: a randomized trial in 10-25-year-old HIV-Seronegative African girls and young women. J Infect Dis. 2013 Jun 1;207(11):1753-63.
NCT00518336 (Publication 1) De Carvalho N, Teixeira J, Roteli-Martins CM, Naud P, De Borba P, Zahaf T, Sanchez N, Schuind A. Sustained efficacy and immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine up to 7.3 years in young adult women. Vaccine. 2010 Aug 31;28(38):6247-6255.
NCT00518336 (Publication 2) Roteli-Martins CM, Naud P, De Borba P, Teixeira JC, De Carvalho NS, Zahaf T, Sanchez N, Geeraerts B, Descamps D. Sustained immunogenicity and efficacy of the HPV-16/18 AS04-adjuvanted vaccine: up to 8.4 years of follow-up. Hum Vaccin Immunother. 2012 Mar;8(3):390-7.
NCT00518336 (Publication 3) Naud PS, Roteli-Martins CM, De Carvalho NS, Teixeira JC, de Borba PC, Sanchez N, Zahaf T, Catteau G, Geeraerts B, Descamps D. Sustained efficacy, immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine: final analysis of a long-term follow-up study up to 9.4 years post-vaccination. Hum Vaccin Immunother. 2014;10(8):2147-2162.
NCT00344032 Bhatla N, Suri V, Basu P, Shastri S, Datta SK, Bi D, Descamps DJ, Bock HL; Indian HPV Vaccine Study Group. Immunogenicity and safety of human papillomavirus-16/18 AS04-adjuvanted cervical cancer vaccine in healthy Indian women. J Obstet Gynaecol Res. 2010 Feb;36(1):123-32. doi: 10.1111/j.1447-0756.2009.01167.x. Erratum in: J Obstet Gynaecol Res. 2010 Apr;36(2):466.
NCT00306241 Ngan HYS, Cheung AN, Tam KF, Chan KK, Tang HW, Bi D, Descamps D, Bock HL. Human papillomavirus-16/18 AS04-adjuvanted cervical cancer vaccine: immunogenicity and safety in healthy Chinese women from Hong Kong. Hong Kong Med J. 2010 Jun;16(3):171-179.
NCT00485732 Kim SC, Song YS, Kim YT, Kim YT, Ryu KS, Gunapalaiah B, Bi D, Bock HL, Park JS. Human papillomavirus 16/18 AS04-adjuvanted cervical cancer vaccine: immunogenicity and safety in 15-25 years old healthy Korean women. J Gynecol Oncol. 2011 Jun 30;22(2):67-75.
NCT00779766 Zhu FC, Chen W, Hu YM, Hong Y, Li J, Zhang X, Zhang YJ, Pan QJ, Zhao FH, Yu JX, Zhang YS, Yang X, Zhang CF, Tang H, Zhang H, Lebacq M, David MP, Datta SK, Struyf F, Bi D, Descamps D; HPV-039 study group. Efficacy, immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine in healthy Chinese women aged 18-25 years: results from a randomized controlled trial. Int J Cancer. 2014 Dec 1;135(11):2612-2622.
NCT00996125 Zhu F, Li J, Hu Y, Zhang X, Yang X, Zhao H, Wang J, Yang J, Xia G, Dai Q, Tang H, Suryakiran P, Datta SK, Descamps D, Bi D, Struyf F. Immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine in healthy Chinese girls and women aged 9 to 45 years. Hum Vaccin Immunother. 2014;10(7):1795-806.
These are pivotal publications that underpin the approval of the vaccine. [22]
It is our belief that these publications [1–13] incompletely reported important methodological details and that twelve [1–12] of thirteen inaccurately described the formulation that the control arm received, necessitating correction of the record.
We intend to restore the written record for these trials in accordance with the principles of the Restoring Invisible and Abandoned Trials (RIAT) initiative, of which we are founders. [14] This restoration will be similar to the restoration of Gardasil trials for which we issued two Calls to Action (11 Jan 2019 and 21 Feb 2019) and for which we recently published our focussed RIAT restoration. [15–17]
Our rationale for correcting the record
By obtaining the available unredacted CSRs for Cervarix, we have determined that the comparator in trials and follow-up studies of the Cervarix vaccine appears to have been an injection containing aluminum hydroxide. It is our assessment that the primary publications of these trials may have misrepresented that an active comparator was used rather than an inert substance (such as saline injection) through the use of the term “placebo-controlled”. We plan to conduct a thorough investigation of the primary publication for each study listed above to determine the extent of this misrepresentation, and further, to determine why an active comparator was used.
The use of a comparator that was neither an inert substance nor an efficacious vaccine against another disease demands explanation. The clinical rationale for such a decision is unclear, as the trial arms do not mimic the real-life choice of deciding whether or not to receive the HPV vaccine, and it is incompatible with established ethical principles regarding the use of placebo in vaccine trials. [18] Furthermore, because aluminum hydroxide is not inert, the choice of aluminum-containing control complicates the interpretation of efficacy and safety results in trials.
Therefore, we consider the omission in journal articles, of any rationale for the selection of aluminum-containing control, to be a form of incomplete reporting (of important methodological details) and believe that the rationale must be reported. We also consider that use of the term “placebo” to describe a non-inert comparator like aluminum hydroxide inaccurately describes the formulation that the control arm received and constitutes an important error that requires correction. If trial participants were told they could receive “placebo” (widely defined as referring to an “inactive” [19, 20] or “inert” [18] substance) without being informed of all non-inert contents of the control arm injection, this raises ethical questions about trial conduct as well.
Scope of our restoration
We will systematically correct the record for all Cervarix trial publications identified above.
Our sources
Our population of trials potentially eligible for restoration is defined as the primary publications of clinical trials and follow-up studies for which we have obtained CSRs from Health Canada and from the GSK Clinical Study Register. Following a ruling in Canadian Federal Court, we have all unredacted CSRs for Cervarix that are in the holdings of Health Canada in our possession. [21]
Questions our restoration aims to answer
1. Has the rationale for using a control arm formulation that contained aluminum hydroxide been documented? If so, where, and what was it?
2. What comprised the control arm formulation in controlled Cervarix trials?
3. How was the control arm formulation described across trial publications, registry entries, CSRs, and informed consent forms?
4. What are the consequences of such a choice for trial participants, and how might it affect the interpretation of the trial results?
References
1. Harper DM, Franco EL, Wheeler C, et al. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. Lancet Lond Engl. 2004;364(9447):1757-1765. doi:10.1016/S0140-6736(04)17398-4
2. Harper DM, Franco EL, Wheeler CM, et al. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet Lond Engl. 2006;367(9518):1247-1255. doi:10.1016/S0140-6736(06)68439-0
3. Skinner SR, Szarewski A, Romanowski B, et al. Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years: 4-year interim follow-up of the phase 3, double-blind, randomised controlled VIVIANE study. Lancet Lond Engl. 2014;384(9961):2213-2227. doi:10.1016/S0140-6736(14)60920-X
4. Denny L, Hendricks B, Gordon C, et al. Safety and immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine in HIV-positive women in South Africa: a partially-blind randomised placebo-controlled study. Vaccine. 2013;31(48):5745-5753. doi:10.1016/j.vaccine.2013.09.032
5. Sow PS, Watson-Jones D, Kiviat N, et al. Safety and Immunogenicity of Human Papillomavirus-16/18 AS04-Adjuvanted Vaccine: A Randomized Trial in 10–25-Year-Old HIV-Seronegative African Girls and Young Women. J Infect Dis. 2013;207(11):1753-1763. doi:10.1093/infdis/jis619
6. De Carvalho N, Teixeira J, Roteli-Martins CM, et al. Sustained efficacy and immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine up to 7.3 years in young adult women. Vaccine. 2010;28(38):6247-6255. doi:10.1016/j.vaccine.2010.07.007
7. Roteli-Martins CM, Naud P, De Borba P, et al. Sustained immunogenicity and efficacy of the HPV-16/18 AS04-adjuvanted vaccine: up to 8.4 years of follow-up. Hum Vaccines Immunother. 2012;8(3):390-397. doi:10.4161/hv.18865
8. Naud PS, Roteli-Martins CM, De Carvalho NS, et al. Sustained efficacy, immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine: final analysis of a long-term follow-up study up to 9.4 years post-vaccination. Hum Vaccines Immunother. 2014;10(8):2147-2162. doi:10.4161/hv.29532
9. Bhatla N, Suri V, Basu P, et al. Immunogenicity and safety of human papillomavirus-16/18 AS04-adjuvanted cervical cancer vaccine in healthy Indian women. J Obstet Gynaecol Res. 2010;36(1):123-132. doi:10.1111/j.1447-0756.2009.01167.x
10. Ngan HYS, Cheung ANY, Tam KF, et al. Human papillomavirus-16/18 AS04-adjuvanted cervical cancer vaccine: immunogenicity and safety in healthy Chinese women from Hong Kong. Hong Kong Med J Xianggang Yi Xue Za Zhi. 2010;16(3):171-179.
11. Kim SC, Song YS, Kim Y-T, et al. Human papillomavirus 16/18 AS04-adjuvanted cervical cancer vaccine: immunogenicity and safety in 15-25 years old healthy Korean women. J Gynecol Oncol. 2011;22(2):67-75. doi:10.3802/jgo.2011.22.2.67
12. Zhu F-C, Chen W, Hu Y-M, et al. Efficacy, immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine in healthy Chinese women aged 18-25 years: results from a randomized controlled trial. Int J Cancer. 2014;135(11):2612-2622. doi:10.1002/ijc.28897
13. Zhu F, Li J, Hu Y, et al. Immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine in healthy Chinese girls and women aged 9 to 45 years. Hum Vaccines Immunother. 2014;10(7):1795-1806. doi:10.4161/hv.28702
14. Doshi P. RIAT Support Center. RIAT Support Center. Accessed June 3, 2020. https://restoringtrials.org/
15. Call to action: RIAT restoration of a previously unpublished methodology in Gardasil vaccine trials. Published online May 14, 2020. Accessed May 19, 2020. https://www.bmj.com/content/346/bmj.f2865/rr-7
16. Doshi P, Bourgeois F, Hong K, et al. Adjuvant-containing control arms in pivotal quadrivalent human papillomavirus vaccine trials: restoration of previously unpublished methodology. BMJ Evid-Based Med. Published online March 17, 2020. doi:10.1136/bmjebm-2019-111331
17. Additional trials within scope: a follow-up to our “Call to action: RIAT restoration of a previously unpublished methodology in Gardasil vaccine trials.” Published online August 10, 2020. Accessed August 10, 2020. http://www.bmj.com/content/346/bmj.f2865/rr-9
18. Rid A, Saxena A, Baqui AH, et al. Placebo use in vaccine trials: recommendations of a WHO expert panel. Vaccine. 2014;32(37):4708-4712. doi:10.1016/j.vaccine.2014.04.022
19. Merck Clinical Trials. Accessed August 4, 2020. https://www.merckclinicaltrials.com/
20. Glossary of Common Site Terms - ClinicalTrials.gov. Accessed August 4, 2020. https://clinicaltrials.gov/ct2/about-studies/glossary
21. Precedent pushing practice: Canadian court orders release of unpublished clinical trial data - The BMJ. Accessed August 4, 2020. https://blogs.bmj.com/bmj/2018/07/19/precedent-pushing-practice-canadian...
22. 2009 - FDA Approves New Vaccine for Prevention of Cervical Cancer. Accessed September 3, 2020. http://wayback.archive-it.org/7993/20170112212440/http://www.fda.gov/New...
Competing interests: FB’s work is supported by a grant from the Burroughs Wellcome Fund and by the Harvard-MIT Center for Regulatory Science. The Laura and John Arnold Foundation funds the RIAT Support Center which supports the salaries of Peter Doshi (PD), Kyungwan Hong (KH), Mark Jones (MJ), Tom Jefferson (TJ), and Anisa Rowhani-Farid (ARF). In addition: PD has received travel funds from the European Respiratory Society (2012) and Uppsala Monitoring Center (2018); grants from the Laura and John Arnold Foundation (2017-20), American Association of Colleges of Pharmacy (2015), Patient-Centered Outcomes Research Institute (2014-16), Cochrane Methods Innovations Fund (2016-18), and UK National Institute for Health Research (2011-14); and is an editor at The BMJ and unpaid member of the Reagan-Udall Foundation for the FDA. KH received the Maryland CERSI Scholar award from the Food and Drug Administration (grant # 5U01FD005946-04). MJ reports research funds from the Cochrane Methods Innovation Fund to assist with providing interim guidance on the inclusion of clinical study reports and other regulatory documents in Cochrane Reviews. He is also deputy coordinating editor for the Cochrane Acute Respiratory Infections Group. TJ was in receipt of a Cochrane Methods Innovations Fund grant to develop guidance on the use of regulatory data in Cochrane reviews (2015-018). In 2014–2016, TJ was a member of three advisory boards for Boehringer Ingelheim. TJ was a member of an independent data monitoring committee for a Sanofi Pasteur clinical trial on an influenza vaccine. TJ is occasionally interviewed by market research companies about phase I or II pharmaceutical products for which he receives fees (current). TJ was a member of three advisory boards for Boehringer Ingelheim (2014-16). TJ was a member of an independent data monitoring committee for a Sanofi Pasteur clinical trial on an influenza vaccine (2015-2017). TJ is a relator in a False Claims Act lawsuit on behalf of the United States that involves sales of Tamiflu for pandemic stockpiling. If resolved in the United States’ favor, he would be entitled to a percentage of the recovery. TJ is co-holder of a Laura and John Arnold Foundation grant for development of a RIAT support centre (2017-2020) and Jean Monnet Network Grant, 2017-2020 for The Jean Monnet Health Law and Policy Network. TJ is an unpaid collaborator to the project Beyond Transparency in Pharmaceutical Research and Regulation led by Dalhousie University and funded by the Canadian Institutes of Health Research (2018-2022). TJ consulted for Illumina LLC on next generation gene sequencing (2019-2020). TJ was the consultant scientific coordinator for the HTA Medical Technology programme of the Agenzia per i Serivizi Sanitari Nazionali (AGENAS) of the Italian MoH (2007-2019). TJ is Director Medical Affairs for BC Solutions, a market access company for medical devices in Europe. TJ is funded by NIHR UK and the World Health Organization (WHO) to update Cochrane review A122, “Physical Interventions to interrupt the spread of respiratory viruses”. TJ is funded by Oxford University to carry out a living review on the transmission epidemiology of COVID-19. Since 2020, TJ receives fees for articles published by The Spectator and other media outlets. ARF and LS have no competing interests to declare.
We have clinical study reports (CSRs) and individual participant data (IPD) for six trials of gabapentin for neuropathic pain. As described in previous publications, there are multiple data sources for gabapentin trials, which report different study and participant characteristics and different results. Broadly, public sources (e.g., journal articles) tend to overstate the benefits of gabapentin and to underestimate its harms.
As part of the Multiple Data Sources (MUDS) study, we requested additional information about these trials from the manufacturer. In response, Pfizer confirmed that all known materials had already been released during litigation and that no further reports were anticipated.
We plan to submit a proposal to the RIAT support Center to restore these misreported trials, focusing specifically on the misreported harms (“adverse events”). If the proposal is successful, we will develop a statistical analysis plan (SAP) for analyzing and reporting harms, publish a comprehensive summary of all observed harms, and publish a summary of the clinical implications of our findings.
Competing interests: Data that will be used in this study were extracted for the MUDS study (Kay Dickersin, PI), which was funded by contract ME 1303 5785 from the Patient-Centered Outcomes Research Institute (PCORI) and a fund established at Johns Hopkins for scholarly research on reporting biases by Greene LLP. Evan Mayo-Wilson receives research support from the Laura and John Arnold Foundation
Call to action: RIAT restoration of two fluoxetine studies of depression in children and adolescents
This is a call to action to restore the reporting of the two pivotal placebo-controlled trials of fluoxetine for depression in children and adolescents (1,2). The clinical study reports of these two trials were submitted by Eli Lilly to drug regulators to obtain marketing authorization.
As these trials were misreported, I intend to restore the written record for them in accordance with the principles of the Restoring Invisible and Abandoned Trials (RIAT) initiative (3). On PubMed, there are no links to letters to the editor related to the two trials.
My rationale for correcting the record
I have copies of the two clinical study reports obtained from the Medicines and Healthcare products Regulatory Agency in the UK: B1Y-MC-HCJE and B1Y-MC-X065 (2549 and 1008 pages, respectively). There are very few redactions in these reports, which are mostly limited to names of people and laboratories. Although the authors of the first publication (1) stated that they undertook the study “to evaluate the comparative efficacy, safety, and tolerability of fluoxetine treatment compared with placebo,” there was virtually nothing in their paper about safety. They used two elaborate checking lists for adverse effects but only reported that, “Side effects, as a reason for discontinuation, were minimal, affecting only 4 patients who were receiving fluoxetine and 1 who was receiving placebo. The side effects leading to discontinuation of fluoxetine treatment were in 3 patients in whom manic symptoms developed and 1 patient who developed a severe rash.” The fact that two of the 48 patients on fluoxetine attempted suicide versus none of 48 on placebo was not mentioned.
In the second trial, 109 versus 110 patients were randomised to fluoxetine and placebo, respectively (2). Headache was the only non-solicited adverse event reported significantly more often on fluoxetine than on placebo. However, the clinical study report tells a different story to the published article. As p-values were calculated for each adverse event separately, these analyses lacked appropriate power. I calculated that treatment-related non-solicited adverse events occurred significantly more often on fluoxetine than on placebo (p = 0.02) and, although absolute numbers were small, several events that predispose to suicide and violence (4) were more common on fluoxetine than on placebo (e.g. abnormal dreams, akathisia, hyperkinesia, delusions, emotional lability and hallucinations). The only data in the article (2) about suicidal events or precursor events to suicide and violence were those that led to treatment discontinuation.
Scope and objectives of the restoration
The restoration will focus on adequate reporting of adverse events, in particular those related to suicide and violence; relevant limitations of the trial that were not reported such as issues with the randomisation and blinding procedures; and missing outcomes, which were common, both for effect and adverse effect measures. The restoration will also compare investigator assessed outcomes with those assessed by the patients.
1 Emslie GJ, Rush AJ, Weinberg WA, Kowatch RA, Hughes CW, Carmody T, Rintelmann J. A double-blind, randomized, placebo-controlled trial of fluoxetine in children and adolescents with depression. Arch Gen Psychiatry 1997;54:1031-7.
2 Emslie GJ, Heiligenstein JH, Wagner KD, Hoog SL, Ernest DE, Brown E, Nilsson M, Jacobson JG. Fluoxetine for acute treatment of depression in children and adolescents: a placebo-controlled, randomized clinical trial. J Am Acad Child Adolesc Psychiatry 2002;41:1205-15.
3 Doshi P, Dickersin K, Healy D, Vedula SS, Jefferson T. Restoring invisible and abandoned trials: a call for people to publish the findings. BMJ 2013;346:f2865.
4 Bielefeldt AØ, Danborg PB, Gøtzsche PC. Precursors to suicidality and violence on antidepressants: systematic review of trials in adult healthy volunteers. J R Soc Med 2016;109:381-92.
Competing interests: No competing interests
We write to issue a call to action to restore the reporting of a randomized clinical trial on evolocumab in patients with cardiovascular disease sponsored by AMGEN (FOURIER trial):
Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS, Pedersen TR, for the FOURIER Steering Committee and Investigatorset al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med 2017;376(18):1713-1722. doi: 10.1056/NEJMoa1615664. ClinicalTrials.gov Identifier: NCT01764633.
We understand this trial was misreported since cardiovascular events were not published in full and also relevant limitations of the trial were disregarded.
We intend to restore the written record for this trial in accordance with the principles of the Restoring Invisible and Abandoned Trials (RIAT) initiative (1).
Our rationale for correcting the record
The protocol of the FOURIER clinical trial reads as follows: “Given that evolocumab is expected to reduce LDL-C by even more than 1.0 mmol (39 mg/dL) in patients already on an intense dose statin therapy (based on phase 1b results), it is expected that the FOURIER study will demonstrate that evolocumab administration will produce a significant reduction of cardiovascular events, compared to placebo, in high risk patients on maximally tolerated atorvastatin background therapy” (protocol synopsis, page 39).
The published trial reports the results on a pre-defined composite cardiovascular primary end point (cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization) and on the following secondary outcomes (2):
- cardiovascular death, myocardial infarction, or stroke (key secondary endpoint)
- death from any cause
- hospital admissions for worsening heart failure
However, in the NEJM publication there is no information on the total cardiovascular events and serious cardiovascular events in the evolocumab group vs placebo.
According to the study protocol, the “Safety Objective” is to evaluate the safety and tolerability of evolocumab, compared with placebo, in subjects with clinically evident cardiovascular disease. The approved version of the protocol (pages 78-79) defines Serious Adverse Effects (SAE) in the same way as the International Conference for Harmonization (ICH) does. At the same time, the protocol indicates that for grade 4 “life threatening” adverse events it was left to the investigator’s judgement to also report these abnormalities as SAE (page 175), which could have led to underestimating this safety outcome.
After patient recruitment had already started, the protocol was amended in order to clarify that all cause death, myocardial infarction, stroke, revascularization, hospitalization for unstable angina, hospitalization for heart failure, and transient ischemic attack will not be considered serious adverse events in this study, but will be handled as efficacy endpoints that the data monitoring committee will be requested to follow. This means that CV events classified as endpoints were not considered as SAEs even though they also met the ICH definition for SAEs. In addition, since CV adverse events were not reported in the NEJM publication, the incidence of overall and serious CV events remains unknown.
The protocol was also amended to have some secondary outcomes switched after the trial had already got started. In the published article there was no mention about this outcome switching carried out during the implementation of the trial, and also relevant potential conflicts of interest of the main author were not reported. According to Amgen transparency disclosures and ProPublica website, the main author of the NEJM publication received payments during 2014-2016 worth over 130,000 US $ for consulting activities directly related to Repatha (evolocumab). However the main author declares having no conflicts of interest in relation to the FOURIER trial.
According to the information in the Clinical Study Report (CSR), the trial failed to secure blinding and this should also be stated among the limitations in the published article.
Scope of our restoration
We aim at restoring the information on cardiovascular events, serious CV adverse events and also show some relevant limitations of the trial that were not reported. If appropriate, events re-adjudication will be carried out to correctly adjudicate and analyze events.
Our sources
On March 27, 2018, the EMA granted Juan Erviti access to the CSR of the FOURIER trial. Over the last year most of the information requested was sent to the researcher and the rest is expected to be received within the next few months. The information already obtained is enough to proceed to the restoration of the trial. Other publicly available sources like Amgen transparency disclosures and ProPublica website will be used to restore the information on potential conflicts of interest.
Our objectives
- To report serious and total CV adverse events according to the ICH definition.
- To report serious and total adverse events according to the ICH definition.
- To re-adjudicate events and re-calculate the results for the primary and secondary outcomes if appropriate.
- To state the real conflicts of interest of the authors in relation to the FOURIER trial, failure to secure blinding and report about the outcome switching carried out during the implementation of the trial.
- Other possible inconsistencies between the results in the CSR and the published article that may arise.
References
1. Doshi P, Dickersin K, Healy D, Vedula SS, Jefferson T. Restoring invisible and abandoned trials: a call for people to publish the findings. BMJ. 2013 Jun 13;346:f2865.
2. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med 2017;376(18):1713-1722. doi: 10.1056/NEJMoa1615664
Competing interests: No competing interests
We write to issue a call to action to restore the reporting of a randomized clinical trial on Plasma Rich in Growth Factors (PRGF-Endoret®) sponsored by BTI Biotechnology Institute. The concerned trial has been cited as follows:
Sánchez M, Fiz N, Azofra J, Usabiaga J, Aduriz Recalde E, Garcia Gutierrez A, Albillos J, Gárate R, Aguirre JJ, Padilla S, Orive G, Anitua E. A randomized Clinical trial evaluating Plasma Rich in Growth Factors (PRGF-Endoret) versus hyaluronic acid in the short-term treatment of symptomatic knee osteoarthritis. Arthroscopy 2012;28(8):1070-8.
This high impact publication, totaling 167 citations as of March 25th, 2019 according to Scopus (https://www.scopus.com), reports the results of a clinical trial of PRGF-Endoret® compared to hyaluronic acid that enrolled 176 patients with knee osteoarthritis. Furthermore, this study was highly influential to the Spanish Medicines Agency (AEMPS) since platelet-rich plasma and derivatives were granted the human medicine category last May 2013 based on the results of the above-mentioned trial.
However, according to the pre-planned authorized protocol, this trial publication has misreported several key methodological issues, which substantially affects the final results and conclusions, and thereby correction of the record is warranted.
We intend to restore the written record for this trial in accordance with the principles of the Restoring Invisible and Abandoned Trials (RIAT) initiative (1).
Our rationale for correcting the record
According to the study protocol (page 5), the primary efficacy outcome is set up as a significant clinical improvement in the pain Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) subscale. In addition, in Section 6.2.3 (page 20) a ‘significant clinical improvement’ is defined as a minimum of 40% decrease in the pain WOMAC subscale compared to the basal estimate (2). The study final report is coherent with the protocol on this issue (page 11) and does not find statistically significant differences between both interventions (pages 15 and 18). However, the corresponding publication (3) does not report the 40% decrease in the pain WOMAC subscale but the 50% decrease in the pain WOMAC subscale. Assuming this new outcome, statistically significant differences were found and publicly reported.
Also, results from several pre-planned secondary outcomes [>40% decrease in pain Visual Analogue Scale (VAS) and Lequesne scales, level of articular mobility (pages 28-29)] are presented in the study final report (pages 21, 24, 34) but not in the published article. Other pre-planned secondary outcomes [≥30% increase in physical function measured by Lequesne and WOMAC scales, quality of life, markers and indicators as C - reactive protein, metalloproteinases, etc. (pages 28-29)] are not provided in the final report or in the publication. Finally, the publication informs about some secondary outcomes, not previously included in the protocol as pre-planned outcomes: Outcome Measures In Rheumatology-Osteoarthritis Research Society International (OMERACT-OARSI) responders, 20% decrease in WOMAC pain score, percentage of change in the score of WOMAC subscales and global scale, percentage of change in Lequesne scale) (3).
On the other hand, in the ‘Results analysis’ section of the protocol (page 41) it is defined that a per-protocol analysis will be carried out. The study final report is also coherent with the protocol on this issue. However, the corresponding publication reports an intention-to-treat analysis instead of a per-protocol analysis (3).
Some other non-justified minor incoherencies have also been identified between the protocol and the final publication, namely the age range for elegibility, Body Mass Index (BMI) inclusion criteria and sample size calculation. Finally, the publication states that ‘all adverse events disappeared in 48 hours’ but, according to Table 4, it appears to be at least two patients in the hyaluronic arm and five patients in the PRGF arm with persistent adverse events (3).
No evidence of any significant amendment to the protocol has been proved to justify these methodological changes.
The authors report in the publication that they have no conflicts of interest in the authorship and publication of this article. However one of the authors is the Scientific Director of the BTI Biotechnology Institute, manufacturer of the PRGF-Endoret®, and others are employees of the company (3). In our view this is a strong conflict of interest that needs to be declared.
Scope of our restoration
Given the important differences between the final report and the publication in terms of interpretation and conclusions, a thorough correction should be done using the pre-specified primary and secondary outcomes, as well as the original per-protocol analysis. Potential conflicts of interest of the authors should also be stated. Any other detected incoherence should also be dealt with. In a second stage, this restoration should lead to revise in-depth other publications directly affected by this misreported trial, such as a meta-analysis published by the same research team (4).
Our sources
Our background material include the trial protocol, study final report and ethics committee approval letter, all of them facilitated by the study contact author on January 14th, 2019. We will conduct a RIAT re-analysis in adherence to the original protocol and the results included in the study final report.
Questions our restoration aims to answer
1. What is the efficacy of PRGF versus hyaluronic acid in the primary outcome preespecified in the protocol according to the data in the original final report?
2. What is the efficacy of PRGF versus hyaluronic acid in the secondary outcomes preespecified in the protocol according to the data in the original final report?
3. What are the results on the primary and secondary outcomes according to a per-protocol analysis instead of an intention-to-treat analysis?
4. What other kind of incoherencies between protocol, final report and publication need to be corrected in the publication to gain in accuracy? After restoring the Methods and Results sections, how should be re-written the Abstract, Discussion and Conclusions sections?
References
1. Doshi P, Dickersin K, Healy D, Vedula SS, Jefferson T. Restoring invisible and abandoned trials: a call for people to publish the findings. BMJ. 2013 Jun 13;346:f2865.
2. Altman R, Brandt K, Hochberg M, Moskowitz R, Bellamy N, Bloch DA, et al. Design and conduct of Clinical trials in patients with osteoarthritis: recommendations from a task force of the Osteoarthritis Research Society. Osteoarthritis and Cartilage 1996;4:217-43.
3. Sánchez M, Fiz N, Azofra J, Usabiaga J, Aduriz Recalde E, Garcia Gutierrez A, Albillos J, Gárate R, Aguirre JJ, Padilla S, Orive G, Anitua E. A randomized Clinical trial evaluating Plasma Rich in Growth Factors (PRGF-Endoret) versus hyaluronic acid in the short-term treatment of symptomatic knee osteoarthritis. Arthroscopy 2012;28(8):1070-8.
4. Anitua E, Sánchez M, Aguirre JJ, Prado R, Padilla S, Orive G. Efficacy and safety of Plasma Rich in Growth Factors intra-articular infiltrations in the treatment of knee osteoarthritis. Arthroscopy 2014;30(8):1006-17.
Competing interests: No competing interests
We issue a call to action to restore the reporting of STAR*D’s six trials [1-6] and summary article reporting 12-month follow-up findings. [7]
STAR*D (NCT00021528) is the largest and most consequential antidepressant study ever conducted. Funded by the National Institute of Mental Health (NIMH) for 35-million $US, STAR*D enrolled 4,041 patients between 2001-2006 who screened positive for major depression while seeking routine medical or psychiatric care and included patients with common medical and psychiatric comorbid conditions thereby increasing the generalizability of its findings.
STAR*D provided up to 4 treatment steps per patient and was designed to give guidance in selecting the best next-step option for patients who fail to gain sufficient relief from their first, and/or subsequent, trial(s). Antidepressants were administered using a system of measurement-based care that assessed symptoms and side-effects each visit to guide aggressive medication dosing “to ensure that the likelihood of achieving remission was maximized and that those who did not reach remission were truly resistant to the medication.”[1, p. 30]
STAR*D evaluated the relative effectiveness of 11 pharmacologically distinct drug–drug combination treatments in five head-to-head comparisons. [2-6] Patients who achieved remission were encouraged to enter one-year free follow-up care, as were responder patients who failed to attain remission but did not want to continue to the next step as this involved changing medication.
STAR*D’s prespecified primary outcome was remission, defined as scoring <8 on the blindly-administered Hamilton Rating Scale of Depression (HRSD). Response was a secondary outcome defined as ≥50% HRSD reduction. STAR*D had 11 additional prespecified secondary outcome measures assessing health, work and social functioning, quality of life, side-effect burden, medical utilization and cost, and personal income. Both the prespecified primary and secondary outcomes were administered at entry into and exit from each treatment step and follow-up months 3, 6, 9, and 12. [8, table 2]
The investigators state, “STAR*D uses a randomized, controlled design to evaluate both the theoretical principles and clinical beliefs that currently guide the management of treatment-resistant depression in terms of symptoms, function, satisfaction, side-effect burden, and health care utilization and cost estimates. Given the dearth of controlled data, results should have substantial public health and scientific significance.” [9, p. 136]
Thirteen years later, STAR*D researchers have still not published steps 1-4 pre/post and follow-up findings for the secondary outcomes as prespecified. Other researchers though have conducted post-hoc analyses using a subset of the secondary outcomes typically focused on special populations. [eg, 10, 11] Elsewhere we document STAR*D researchers evidenced multiple protocol violations with each violation having an inflationary effect on reported remission and response rates. [12-14]
Given STAR*D’s “substantial public health and scientific significance,” we intend to restore the record for these trials following the principles of the Restoring Invisible and Abandoned Trials (RIAT) initiative. [15]
Our rationale for correcting the record
Apparent protocol violations include:
• Following data collection and without disclosure, substituting a non-blinded/clinic-administered assessment that was used to guide care as the secondary outcome to report remission rates and sole outcome to report response rates in steps 1‐4, and sole outcome measure to report remission and response rates in the summary article. This switch occurred despite STAR*D’s protocol specifically excluding all non-blinded/clinic-administered assessments from use as research outcome measures. [8, p. 47-48]
• Used data from 931 patients deemed ineligible for analysis in step-1 in their steps 2-4 and summary articles without clear disclosure: 607 because these patients’ <14 HRSD score signified at most only mild depressive symptoms when entering the study as well as 324 patients without a blindly-administered baseline HRSD. [1, figure 1] Furthermore, our analysis of STAR*D’s dataset discovered that 99 of the 607 patients scored <8 on their baseline HRSD—STAR*D’s remission criterion. Despite scoring as not depressed at study outset, the outcome data from many of these 99 patients were included in the steps 2-4 articles and all were included in the summary article.
• Failed to disclose that all patients started on citalopram in their baseline visit while excluding from analysis the 370 who then dropped out, [1, figure 1; 7, figure 1] despite the step-1 article stating, “our primary analyses classified patients with missing exit HRSD scores as nonremitters a priori.” [1, p. 34] These 370 early dropout patients did not have an exit HRSD and therefore should have been counted as treatment failures as prespecified.
Recently, we published a step-1 reanalysis using NIMH’s STAR*D dataset. [14] This analysis found substantial reductions in remission and response rates using the blindly-administered HRSD. While step-1 authors claimed “the response and remission rates in this highly generalizable sample with substantial axis I and axis III comorbidity closely resemble those seen in 8-week efficacy trials,” [1, p. 28] our analysis found citalopram’s actual real-world effectiveness was approximately half that reported in efficacy trials.
Surprisingly, an exploratory analysis of step-2’s dataset discovered 117 patients scoring <8 on the HRSD at entry into step-2 yet were included in the step-2 analyses. In other words, 117 patients scored as remitted prior to starting their step-2 medication yet were included in STAR*D’s medication switch [2] and augmentation [3] articles. This occurred despite STAR*D researchers prespecifying, “participants who begin a level with HRSD <8 will be excluded from analyses.” [9, p. 130]
The fact that there were no reported statistical differences in remission and response rates for any of STAR*D’s five head-to-head trials of 11 chemically-distinct medications/medication combinations—and therefore providing no evidence-based guidance for the next best medication option after a failed trial—may be due to these protocol violations versus what actually occurred had the research protocol been followed.
Scope of our restoration
Given the unreported deviations from STAR*D’s protocol, an accurate restoration using the prespecified primary and secondary outcome measures for steps 1-4 and follow-up is essential to understanding the true risks and benefits of each STAR*D treatment, and determine whether to embrace STAR*D’s investigators repeated claims of the superiority of their measurement-based, treat-to-remission, model of care.
Our sources
We will conduct a RIAT reanalysis of the patient-level data in adherence to the original protocol and statistical analysis plan obtained from the NIMH Data Archive unless STAR*D’s authors publicly commit to do so. [17]
Questions our restoration aims to answer
1. What is the fidelity between steps 1-4 published outcomes compared to those from the restored patient-level data using the prespecified outcome measures, inclusion for analysis criteria, and statistical plan?
2. What are the comparative outcomes for steps 2-4 head-to-head trials using the prespecified outcome measures, inclusion criteria, and statistical plan?
3. What are the comparative outcomes during follow-up using the prespecified outcome measures, inclusion criteria, and statistical plan?
References:
1. Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, Norquist G, Howland RH, Lebowitz B, McGarth PJ, Shores-Wilson K, Biggs MM, Balasubramani GK, Fava M. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163:28–40.
2. Rush AJ, Trivedi MH, Wisniewski SR, Stewart JW, Nierenberg AA, Thase ME, Ritz L, Biggs MM, Warden D, Luther JF, Shores-Wilson K, Niederehe G, Fava M. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med. 2006;354:1231–1242.
3. Trivedi MH, Fava M, Wisniewski SR, Thase ME, Quitkin F, Warden D, Ritz L, Nierenberg AA, Lebowitz BD, Biggs MM, Luther JF, Shores-Wilson K, Rush AJ. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354:1243–1252.
4. Fava M, Rush AJ, Wisniewski SR, Nierenberg AA, Alpert JE, McGrath PJ, Thase ME, Warden D, Biggs MM, Luther JF, Niederehe G, Ritz L, Trivedi MH. A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: a STAR*D report. Am J Psychiatry. 2006;163:1161–1172.
5. Nierenberg AA, Fava M, Trivedi MH, Wisniewski SR, Thase ME, McGrath PJ, Alpert JE, Warden D, Luther JF, Niederehe G, Lebowitz BD, Shores-Wilson K, Rush AJ. A comparison of lithium and T3 augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry. 2006;163:1519–1530.
6. McGrath PJ, Stewart JW, Fava M, Trivedi MH, Wisniewski SR, Nierenberg AA, Thase ME, Davis L, Biggs MM, Shores-Wilson K, Luther JF, Niederehe G, Warden D, Rush AJ. Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medications trials for depression: a STAR*D report. Am J Psychiatry. 2006;163:1531–1541.
7. Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum JF, Sackheim HA, Kupfer DJ, Luther J, Fava M. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905–1917.
8. National Institute of Mental Health (NIMH). Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Research Protocol. Washington (DC): NIMH; revised June 28, 2002. Received October 1, 2010, from NIMH following a request under the Freedom of Information Act.
9. Rush AJ, Fava M, Wisniewski SR, Lavori PW, Trivedi MH, Sackeim HA, Thase ME, Nierenberg AA, Quitkin FM, Kashner TM, Kupfer DJ, Rosenbaum JF, Alpert J, Stewart JW, McGrath PJ, Biggs MM, Shores-Wilson K, Lebowitz BD, Ritz L, Niederehe G. Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design. Control Clin Trials. 2004;25:119–142.
10. IsHak WW, Mirocha J, Christensen S, Wu F, Kwock R, Behjat J, Pi S, Akopyan A, Peselow ED, Cohen RM, Elashoff D. Patient-reported outcomes of quality of life, functioning, and depressive symptom severity in major depressive disorder comorbid with panic disorder before and after SSRI treatment in the STAR*D trial. Depress Anxiety. 2014;31:707–716.
11. IsHak WW, Steiner AJ, Klimowicz A, Kauzor K, Dang J, Vanle B, Elzahaby C, Reid M, Sumner L, Danovitch I. Major depression comorbid with medical conditions: analysis of quality of life, functioning, and depressive symptom severity. Psychopharmacol Bull. 2018;48:8–25.
12. Pigott HE, Leventhal AM, Alter GS, Boren JJ. Efficacy and effectiveness of antidepressants: current status of research. Psychother Psychosom. 2010;79:267–279.
13. Pigott HE. STAR*D: a tale and trial of bias. Ethical Hum Psychol Psychiatry. 2011;13:6–28.
14. Pigott, HE. The STAR*D trial: It’s time to reexamine the clinical beliefs which guide the treatment of major depression. Canadian J Psychiatry. 2015;60:9–13.
15. Doshi P, Dickersin K, Healy D, Vedula SS, Jefferson T. Restoring invisible and abandoned trials: a call for people to publish the findings. BMJ. 2013 Jun 13;346:f2865.
16. Kirsch I, Huedo-Medina TB, Pigott HE, Johnson B. Do outcomes of clinical trials resemble those “real world” patients? A re-analysis of STAR*D antidepressant data. Psychology of Consciousness: Theory, Research, and Practice. 2018 https://doi.org/10.1037/cns0000164
17. NIMH Data Archive available at: https://ndar.nih.gov/edit_collection.html?id=2148
Competing interests: No competing interests
On January 11, 2019, we issued a call to action to restore the reporting of multiple trials in Merck’s clinical development program for quadrivalent human papillomavirus (HPV) vaccine (Gardasil) vaccine [1]. In our statement, we had identified problems in the reporting of two Gardasil trials (FUTURE II [NCT00092534] and FUTURE III [NCT00090220]). However we noted that we would begin working on the matter systematically, and “may therefore discover additional trials in need of restoration for the same reason.”
We have now finished assessing all clinical study reports received from the European Medicines Agency, as per our protocol [2], and identified a further three trials (and their respective publications) which are in need of restoration for the same reason. The three additional trials are:
V501-012 (NCT00092482), published as Garland SM, Steben M, Hernandez-Avila M, Koutsky LA, Wheeler CM, Perez G, et al. Noninferiority of antibody response to human papillomavirus type 16 in subjects vaccinated with monovalent and quadrivalent L1 virus-like particle vaccines. Clin Vaccine Immunol. 2007 Jun;14(6):792-5. https://doi.org/10.1128/CVI.00478-06
V501-013 (NCT00092521), published as Garland SM, Hernandez-Avila M, Wheeler CM, Perez G, Harper DM, Leodolter S, et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med. 2007 May 10;356(19):1928-43. https://doi.org/10.1056/NEJMoa061760
V501-020 (NCT00090285), published as Giuliano AR, Palefsky JM, Goldstone S, Moreira ED Jr, Penny ME, Aranda C, et al. Efficacy of quadrivalent HPV vaccine against HPV Infection and disease in males. N Engl J Med. 2011 Feb 3;364(5):401-11. https://doi.org/10.1056/NEJMoa0909537
References
[1] Doshi et al. Call to action: RIAT restoration of a previously unpublished methodology in Gardasil vaccine trials. 11 January 2019. https://www.bmj.com/content/346/bmj.f2865/rr-7
[2] Description and rationale for standalone aluminum-containing control arms in Gardasil vaccine trials: restoration of previously unpublished methodology: protocol and procedural manual. 5 Dec 2018. https://doi.org/10.17605/OSF.IO/234KW
Competing interests: The Laura and John Arnold Foundation funds the RIAT Support Center which supports the salaries of Doshi, Jefferson, Jones, Bourgeois, Spence, Shamseer (until 2018), and Hong. In addition: Peter Doshi has received travel funds from the European Respiratory Society (2012) and Uppsala Monitoring Center (2018); grants from the Laura and John Arnold Foundation (2017-20), American Association of Colleges of Pharmacy (2015), Patient-Centered Outcomes Research Institute (2014-16), Cochrane Methods Innovations Fund (2016-18), and UK National Institute for Health Research (2011-14); and is an editor at The BMJ and unpaid member of the Reagan-Udall Foundation for the FDA. Tom Jefferson (TJ) was a recipient of a UK National Institute for Health Research grant for a Cochrane review of neuraminidase inhibitors for influenza. In addition, TJ receives royalties from his books published by Il Pensiero Scientifico Editore, Rome and Blackwells. TJ is occasionally interviewed by market research companies about phase I or II pharmaceutical products. In 2011-13, TJ acted as an expert witness in litigation related to the antiviral oseltamivir, in two litigation cases on potential vaccine-related damage (including the vaccine Pandemrix (2015-2017) and in a labour case on influenza vaccines in healthcare workers in Canada. He has acted as a consultant for Roche (1997-99), GSK (2001-2), Sanofi-Synthelabo (2003), and IMS Health (2013).In 2014 he was retained as a scientific adviser to a legal team acting on oseltamivir. TJ has a potential financial conflict of interest in the drug oseltamivir. In 2014-16, TJ was a member of three advisory boards for Boerhinger Ingelheim. TJ was holder of a Cochrane Methods Innovations Fund grant to develop guidance on the use of regulatory data in Cochrane reviews. TJ was a member of an independent data monitoring committee for a Sanofi Pasteur clinical trial on an influenza vaccine. Between 1994 and 2013, TJ was the coordinator of the Cochrane Vaccines Field. TJ was a co-signatory of the Nordic Cochrane Centre Complaint to the European Medicines Agency (EMA) over maladministration at the EMA in relation to the investigation of alleged harms of HPV vaccines and consequent complaints to the European Ombudsman. TJ is co-holder of a John and Laura Arnold Foundation grant for development of a RIAT support centre (2017-2020) and Jean Monnet Network Grant, 2017-2020 for The Jean Monnet Health Law and Policy Network. TJ is an unpaid collaborator to the project Beyond Transparency in Pharmaceutical Research and Regulation led by Dalhousie University and funded by the Canadian Institutes of Health Research (2018-2022). Mark Jones was a co-investigator on a UK National Institute for Health Research grant for a Cochrane review of neuraminidase inhibitors for influenza; was a co-recipient of a Cochrane Methods Innovations Fund grant to develop guidance on the use of regulatory data in Cochrane reviews; and is a paid consultant on a John and Laura Arnold Foundation grant for development of a RIAT Support Center (2017-2020). LS, HL, FB, KH: no competing interests to declare. OS was a recipient of a Maryland CERSI Scholar award from the Food and Drug Administration (grant #1U01FD005946).
Doshi and colleagues are concerned, understandably, at the use of control injections in vaccine trials, that are not true placebos. (1)
Perhaps there would be even more concern if people understood that such practices are not unusual, in vaccine trials.
The nature of any control injections, in vaccine trials, is sometimes difficult to ascertain, as Doshi and colleagues’ letter suggests.
In his chapter on vaccine safety, Moskowitz lists the sixteen vaccines that were mandated in the USA, in 2017. (2)
Four of the vaccines were subject to trials that used unspecified “placebos” as controls.
Five of the vaccines had no record of controlled safety studies.
Six of the vaccines were subject to trials where other vaccines were given as the control injections.
In the case of one vaccine, the control injection was a “placebo”, phenol 0.25%.
1 https://www.bmj.com/content/346/bmj.f2865/rr-7
2 Richard Moskowitz, MD, Vaccines, a reappraisal. Skyhorse Publishing, 2017. (pp34 et seq)
Competing interests: No competing interests
When it comes to aluminium adjuvants are babies more robust than young women?
Dear Editor
The call by Doshi et al for the restoration of Cervarix trials is welcome [1]. I would point out that the position with other vaccines, particularly infant vaccines is not obviously better [2]. Vaccines repeatedly given to infants in their first year [3] such as Infanrix Hexa, Prevenar 13 and Bexsero all contain aluminium salts [4,5,6]. I note too the warning of Christopher Exley 'An aluminium adjuvant in a vaccine is an acute exposure to aluminium' [7]. Meanwhile, for whatever reason our schools are drowning in an ever increasing tide of neurological impairment, for which no official explanation is ever forthcoming [8].
When previously healthy young women become invalided it is rightly a cause for remark and deep concern but what about all those young children who are never going to make it? The problem is not firstly that the system cannot provide for them (and it is under critical pressure) but where are they all coming from? Is there something we are doing wrong? If aluminium adjuvants represent a hazard to young women, what about infants - are they so much more robust?
[1] Doshi et al, 'Call to action: RIAT restoration of a previously unpublished methodology in Cervarix vaccine trials', 5 October 2020, https://www.bmj.com/content/346/bmj.f2865/rr-15
[2] John Stone, 'Re: Response to John Stone (2019 Jul 24)',29 July 2019, https://www.bmj.com/content/365/bmj.l4291/rr-37
[3] https://vk.ovg.ox.ac.uk/vk/uk-schedule
[4] Section 2 https://www.medicines.org.uk/emc/medicine/33313#gref
[5] Section 2 https://www.medicines.org.uk/emc/medicine/22689/SPC/Prevenar+13+suspensi...
[6] Section 2 https://www.medicines.org.uk/emc/product/5168/smpc#gref
[7] Christoper Exley, 'An aluminium adjuvant in a vaccine is an acute exposure to aluminium', J Trace Elem Med Biol
. 2020 Jan;57:57-59. doi: 10.1016/j.jtemb.2019.09.010.
[8] Responses to Wise, 'Social care: pressure mounts for urgent and radical reform', https://www.bmj.com/content/366/bmj.l4564/rapid-responses
Competing interests: AgeofAutism.com, an on-line daily journal, concerns itself with the potential environmental sources for the proliferation of autism, neurological impairment, immune dysfunction and chronic disease. I receive no payment as UK Editor