Saturday, October 31, 2015
Monday, October 05, 2015
Sunday, October 04, 2015
Wednesday, July 29, 2015
Monday, July 20, 2015
Here is a quick note about yesterday's hearing. Judgment is expected next week.
The judge grasped the importance of trial registration and when he took into account our and the HRA's evidence on legal and ethical obligations to register trials he found that Richmond was left with an extraordinarily narrow argument. It seems the case will come down to some words in a Q&A on HRA's website that wasn't amended at the same time as the sponsors' declaration was. And then whether the ambiguity was significant.
We are so pleased we decided to intervene in the case. The court could find for Richmond on this very narrow point but it ended up exactly where we thought it should be: a principled discussion in which the judge seemed to grasp the issues well, the removal of Richmond’s broad claims that no registration was legally required and that the HRA was acting unlawfully, and alighting on a narrow matter for decision that will not impact on how trials are run or on the EU rules coming into force next year. Of course we would have liked the case refused altogether instead of it wasting public funds, which will be a lot if HRA has to pay Richmond's costs.
Based on what was said in court, we are hopeful too that the court will find that the HRA has been going about its proper business promoting clinical trial registration. We are pleased that the judge ignored Richmond's attempts to discredit AllTrials, and in fact that these appeared to backfire.
We will share the transcript of yesterday's hearing as soon as we have it. I think you'll enjoy reading it!
When the judge at the hearing yesterday heard that the HRA does not impose any sanctions on trial sponsors who don't register their trials properly he said, "well, they should."
Our legal team was amazing - solicitor Robert Dougans and barrister Jonathan Price - before during and after. If any of you read L Phillips' recent speech asking where are the lawyers who are motivated above all by the pursuit of justice, well we know them.
(Tracey Brown is especially grateful for their patience with her unceasing flow of notes and questions)
Also yesterday, the pharmaceutical industry body EMIG said that Richmond's actions do not represent the views of the rest of industry. Mark Edwards, the CEO, said that the case could have a disastrous effect on the industry. Read EMIGs letter here. It contradicts Richmond's claim to the court that its concerns are representative. Some of you have told us that but EMIG said it publicly, which matters.
Thank you so much to those who came to court yesterday and sent messages of support. As well as the judgment, look out for some other big news stories from AllTrials next week: we can't wait to tell you what your support has helped to achieve.
Director of Campaigns
Sense About Science
Science and evidence in the hands of the public
Wednesday, July 08, 2015
Síle and James
LONDON, EC1R 0DP
Thursday, June 25, 2015
We hoped to tell you more about the case Richmond Pharmacology is bringing against the HRA. That's not been straightforward. Richmond has now changed their argument three times and has altogether abandoned some arguments it relied upon earlier, so getting to grips with what is at stake has been difficult and time consuming for us and for our lawyers.
At the beginning of this week it looked as though Richmond had narrowed the case down to a technical argument about the wording of HRA’s guidelines which only applied for a period of 10 days earlier this year.
Just as the issues seemed to be narrowing, Richmond then asked the Court not to allow AllTrials to be heard. We had written to Richmond and the HRA outlining our planned argument to the court and inviting their response. HRA replied to us, Richmond did not. Instead they went straight to the Judge and asked him not to hear us.
And then yesterday we saw that Richmond has asked the Court at the very last minute to rule on something huge. They want the Court to declare that no trial sponsor or person running a trial has any legal requirement to publicly register any clinical trial unless the sponsor has given a legally binding commitment to do so, or an ethics committee has asked them to do so for every trial. So now the Court is being asked to rule not on the specifics of the case but on a much broader point.
Richmond has asked the Court for a hastily arranged hearing in Manchester on Monday where they will ask to seek that declaration as part of the case. This is after they have warned the court that AllTrials' references to international rules and protocols are irrelevant and will only add to their costs!
We need to be there on Monday to make it clear to the Court that it is being asked to rule on something that has real ramifications beyond this case. If Richmond win, this would go in the face of international laws, regulations, professional standards and the ethical rules of research. If such a declaration was made it would shatter the progress towards transparency made by AllTrials and the progress made internationally before AllTrials even started.
Today we are writing our submission to the Court to be allowed to speak on Monday. We’ll tell you more as soon as we know it. We have only been able to do this because hundreds of you have sent support, encouragement and donations. Thank you.
Sense About Science
Science and evidence in the hands of the public
Tuesday, June 23, 2015
Last week there was extensive news coverage of a leaked letter written by the chief medical officer to the Academy of Medical Sciences. This letter focused especially on concerns around statins and oseltamivir (Tamiflu) and asked the academy for an “authoritative independent report looking at how society should judge the safety and efficacy of drugs.”1 The academy has since announced that it is convening a working group on the subject.
With any such report there are two major risks. The first is a focus on “trust” or even—as a worst case—false reassurance for well documented problems. We do not believe the academy will choose this path. But there is another, bigger risk: the academy may accept shortcomings in the evidence as somehow inevitable. Here there are good grounds for concern. The academy has already announced that its work “will explore how evidence that originates from different sources (e.g. randomised clinical trials and observational data) are used to make decisions about the safety and efficacy of drugs and medical interventions.”2
Focusing solely on existing trials and observational studies would represent a failure of vision and ambition in an era when medicine has both the need and the opportunity to innovate. Well documented problems exist in the funding and prioritisation of research, the conduct of trials, the withholding of results, the dissemination of evidence, and its implementation with patients. Here we briefly examine six domains where the academy could call for simple practical improvements that would address legitimate concerns.
Publication bias—We conduct trials to detect modest differences, and spend vast amounts of money specifically to exclude bias, yet we allow that bias to flood back in through selective publication.3 4 Eminent bodies writing reports will not fix this, but practical action will. We need new funding for simple systematic work to audit which trials are unreported, to highlight the best and worst performers, and to shine a light on withheld studies.5
Independent trials—A recent cohort study found that 97% of head to head trials sponsored by industry give results that favour the sponsor’s drug.6 Doctors and patients are right to want independent trials. On statins and oseltamivir, there are two clear opportunities, and here we declare our own conflicts. With colleagues, one of us (CH) first proposed a trial of oseltamivir in a pandemic in 2009; the other (BG) first proposed a trial of statins examining side effects over a year ago. In both cases we could have the answer by now.
Cost of trials—Replication will be possible only if the cost of conducting trials is radically reduced. Much of this cost is driven by disproportionate regulation around trials of routinely used treatments.7 The National Institute for Health and Care Excellence’s guidance on cholesterol argues for head to head trials in low risk populations; this would require over 100 000 participants, followed up for a decade. Such trials can practically be delivered only by reducing the expensive and disproportionate regulatory burden,7 embedding them in everyday clinical care and gathering follow-up data from existing electronic health records.8
Better evidence—Treatments are routinely approved after trials with only surrogate outcomes.9 Drugs are then extensively promoted, at the moment of approval, when evidence on real world outcomes is paradoxically at its weakest. We could encourage better evidence by, for example, compelling companies to follow-up all phase III trial participants until real world benefits emerge, considering routine randomisation for newly approved drugs when benefits are unclear, and bartering with either patent extension or choice of the start date for market exclusivity. These suggestions would come at minimal cost and deliver more comprehensive data on treatment effects.
Shared decision making—Concern over statins has recently been reawakened by the introduction of a financial incentive for general practitioners to prescribe the drugs to low risk patients. This is ill judged because patients’ informed choices vary widely.10 11 An incentive to prescribe a treatment that many adequately informed patients do not want undermines informed decision making and inflicts avoidable reputational harm on the profession. If instead we incentivise shared decision making then—for the same financial outlay—best practice will be recognised, rewarded, and laid down in the everyday templates of what doctors do.12
Declare conflicts of interest—Declaration of conflicts of interest is currently chaotic, inconsistent, and incomplete. We clearly need a central system of declarations, ideally maintained by the General Medical Council.13 Conflicts, however, become particularly salient when evidence is unclear: when decisions about which treatment works best are made on the basis of a speculative, superficially plausible narrative about a drug’s mechanism of action, or on the interpretation of weak, confounded, observational data when randomised trials are feasible. If we are able to generate better evidence and ensure that we see the complete evidence, then competing interests—although they must always be declared—will become less salient.
This is just a brief tour of six domains, and there is much more to be done. Most of our suggestions are rapidly deliverable. Some require modest funding; most do not. Some require legislative changes. But we should remember that evidence based medicine, in its true modern incarnation, has a relatively short history and that when randomised trials were first introduced they were often regarded as a transgressive, expensive, unnecessary, and unwelcome challenge to medical authority.14 The public is increasingly aware of the shortcomings we collectively tolerate in the evidence base for clinical practice. We now have the opportunity to use public frustration as fuel to update our implementation of evidence based medicine in the light of new technology and get our house in order. To restrict a review of these problems to the interpretation of inadequate existing data—as the academy apparently proposes—would be recklessly backward looking.
Cite this as: BMJ 2015;350:h3397
Competing interests: We have read and understood BMJ policy on declaration of interests and declare BG and CH are founders of the AllTrials campaign calling for all trials to report their results. BG receives funding from the Wellcome Trust and the Laura and John Arnold Foundation and income from speaking, writing, and broadcasting on problems in science and medicine. CH has received funding from a UK National Institute for Health Research grant (HTA—10/80/01 Update and amalgamation of two Cochrane reviews: neuraminidase inhibitors for preventing and treating influenza in healthy adults and children www.nets.nihr.ac.uk/projects/hta/108001). CH also receives occasional payments for running educational courses at the University of Oxford (see www.phc.ox.ac.uk/team/researchers/carl-heneghan for full details).
Provenance and peer review: Commissioned; not externally peer reviewed.
↵Wise J. England’s chief medical officer asks for review of drug evaluation in wake of statins controversy. BMJ2015;350:h3300.FREE Full Text
↵Academy of Medical Sciences. Academy launches new project on evaluating evidence. Press release, 16 Jun 2015. www.acmedsci.ac.uk/more/news/evaluating-evidence-launch/.
↵Schmucker C, Schell LK, Portalupi S, et al. Extent of non-publication in cohorts of studies approved by research ethics committees or included in trial registries. PLoS One2014;9:e114023.CrossRefMedline
↵Song F, Parekh S, Hooper L, et al. Dissemination and publication of research findings: an updated review of related biases. Health Technol Assess2010;14(8).iii, ix-xi,1-193.
↵Goldacre B. How to get all trials reported: audit, better data, and individual accountability. PLoS Med2015;12:e1001821.CrossRefMedline
↵Flacco ME, Manzoli L, Boccia S, et al. Head-to-head randomized trials are mostly industry sponsored and almost always favor the industry sponsor. J Clin Epidemiol2015;68:811-20.CrossRefMedline
↵Van Staa T-P, Dyson L, McCann G, et al. The opportunities and challenges of pragmatic point-of-care randomised trials using routinely collected electronic records: evaluations of two exemplar trials. Health Technol Assess2014;18:1-146.CrossRef
↵Van Staa T-P, Goldacre B, Gulliford M, et al. Pragmatic randomised trials using routine electronic health records: putting them to the test. BMJ2012;344:e55.FREE Full Text
↵Yudkin JS, Lipska KJ, Montori VM. The idolatry of the surrogate. BMJ2011;343:d7995.FREE Full Text
↵Fontana M, Asaria P, Moraldo M, et al. Patient-accessible tool for shared decision making in cardiovascular primary prevention: balancing longevity benefits against medication disutility. Circulation2014;129:2539-46.Abstract/FREE Full Text
↵Van Staa T-P, Smeeth L, Ng ES-W, Goldacre B, Gulliford M. The efficiency of cardiovascular risk assessment: do the right patients get statin treatment? Heart Br Card Soc2013;99:1597-602.Abstract/FREE Full Text
↵Goldacre B, Smeeth L. Mass treatment with statins. BMJ2014;349:g4745.FREE Full Text
↵McCartney M, Goldacre B, Chalmers I, et al. Why the GMC should set up a central registry of doctors’ competing interests. BMJ2014;348:g236.FREE Full Text
↵Blythe M, Cochrane A. One man’s medicine: an autobiography of Professor Archie Cochrane. BMJ Publishing, 1989.
Friday, June 12, 2015
Science and evidence in the hands of the public
Thursday, June 11, 2015
Sidney Wolfe writes in the BMJ - AllTrials - Selective clinical trial reporting: betraying trial participants, harming patients
Reporting biases found in trials of cardiovascular devices
Reporting biases in published trials were first identified in 1986.1 Published randomized studies of combination chemotherapy compared with treatment with an alkylating agent as first line treatment for ovarian cancer showed a significant survival advantage for combination chemotherapy. Unpublished cancer trial registry data from the same studies, however, showed no such advantage.2 Similarly, in the treatment of multiple myeloma, registry data suggested a smaller survival advantage for combination chemotherapy (over prednisone and an alkylating agent) than the results of published studies. The author who reported the discrepancy concluded that his findings “demonstrate the value and importance of an international registry of all clinical trials.”1Subsequent evidence for biased and selective reporting included prompt or delayed publication depending on whether trial results were positive or negative3 and more favorable results and conclusions in published studies funded by industry than in those funded independently.4
The linked paper by Chang and colleagues (doi:10.1136/bmj.h2613) shows similar reporting biases in trials of medical devices.5 The authors found worrying differences between trial information submitted to the US regulator (the Food and Drug Administration) and trial information reported in medical journals. Among 177 studies of 106 high risk cardiovascular devices submitted to the FDA, fewer than half were published, and fewer than half the published studies (45%) reported primary results that precisely matched the results in submissions to the regulator. Among the published primary results, 11% (17) were judged to be “substantially different” from those submitted to the FDA. The authors concluded that “even when trials are published, the study population, primary endpoints, and results can differ substantially from data submitted to the FDA.”5
Most studies of reporting biases have examined differences in efficacy between unpublished clinical trial data and journal publication data but evidence now exists of under-reporting of adverse events. A recent BMJ editorial cites “the growing body of research on reporting biases, which documents the gross under-reporting of adverse event data in such [medical journal] sources.”6
Unfortunately, selective reporting of clinical trial data in medical journals also extends to companies’ selective non-reporting of safety data to the FDA. In 2012, the US Department of Justice announced that “GSK [GlaxoSmithKline] has agreed to plead guilty to failing to report data to the FDA and has agreed to pay a criminal fine in the amount of $242,612,800 for its unlawful conduct concerning Avandia . . . The United States alleges that, between 2001 and 2007, GSK failed to include certain safety data about Avandia, a diabetes drug, in reports to the FDA that are meant to allow the FDA to determine if a drug continues to be safe for its approved indications and to spot drug safety trends.”7
Efforts to increase the public availability of clinical trial data to prevent the serious public health consequences of overstating benefits and understating risks have triggered strong industry opposition. In 2012 the former executive director of the European Medicines Agency (EMA), Guido Rasi, committed the regulator to “proactive publication of clinical-trial data, once the marketing-authorisation process has ended.” He added “We are not here to decide if we publish clinical-trial data, but how.”8 Two pharmaceutical companies sued the EMA to prevent disclosure, and the EMA has watered down its original plans.9
Beyond adverse effects on patients of selective reporting in medical journals, the absence of publicly available data from clinical trials violates an important ethical principle of the Declaration of Helsinki: “Researchers have a duty to make publicly available the results of their research . . . Negative and inconclusive as well as positive results must be published or otherwise made publicly available.”10 Many people participate in research because they trust that the published results might improve the health of the general population.
Ignoring the Declaration of Helsinki, in 2013 the Pharmaceutical Research and Manufacturers of America (PhRMA) urged the US government to influence the European Union against the EMA’s data disclosure policy. In a letter to a US trade representative, PhRMA wrote that “Disclosure of companies’ non-public data submitted in clinical and pre-clinical dossiers and patient-level data risks damaging public health and patient welfare.”11
It is clear that the reverse is true. Non-disclosure is far more damaging. The letter of rebuttal from leaders of the high profile campaign for public registration and reporting of all trial results (AllTrials) reads,
“The world is moving towards a recognition that hiding information about what was done and what was found in clinical trials is an abuse of trial participants’ trust and exposes patients to unnecessary harm.”12
I, and many others, agree.
Cite this as: BMJ 2105;350:h2753
Simes RJ. Publication bias: the case for an international registry of clinical trials. J Clin Oncol 1986;4:1529-41.
US Department of Health and Human Services: compilation of experimental cancer therapy protocol summaries. NIH publication, Government Printing Office, 1977-1983.
Stern JM, Simes RJ. Publication bias: evidence of delayed publication in a cohort study of clinical research projects. BMJ 1997;315:640.
Lundh A, Sismondo S, Lexchin J, Busuioc OA, Bero L. Industry sponsorship and research outcome. Cochrane Database Syst Rev 2012;12:MR000033.
Chang L, Dhruva SS, Chu J, Bero LA, Redberg RF. Selective reporting in trials of high risk cardiovascular devices: cross sectional comparison between premarket approval summaries and published reports.BMJ2105:350;h2613.
Doshi P, Zito J, dosReis S.Digging for data on harms in duloxetine trials. It’s time for policy makers to get serious about drug related harms. BMJ2014;348:g3578.
Torjesin I. European Ombudsman ramps up action against European Medicines Agency over data transparency plans. BMJ2014;348:g3733.http://www.bmj.com/content/350/bmj.h2753?
Tuesday, May 26, 2015
Friday, May 01, 2015
As part of his research into the PBD phenomenon, he noticed hundreds of internal pharmaceutical industry documents publicly released from court cases against pharmaceutical firms by State and Federal Attorney Generals in the USA. These documents concurred with findings of the US Senate "Grassley Commission" into conflicts of interest between the pharmaceutical industry and academic medicine.
In collaboration with A/Prof Glen Spielmans, psychologist from Minnesota, they researched over 400 internal pharmaceutical documents regarding psychotropic medications. They published an article in 2010 in the Journal of Bioethical Inquiry titled "From Evidence-Based Medicine to Marketing-Based Medicine: Evidence from Internal Industry Documents". These documents reveal efforts at "disease-mongering" to expand markets e.g. by increasing the number of people diagnosed with "bipolar disorder"; marketing strategies to influence "customers" i.e. physicians, other health professionals and government regulators; and manipulation of the published medical literature to maximise positive findings and minimise or hide negative findings re manufacturers' medications.
The past few years have witnessed a global awakening in the health professions, lay public and government also - to the fact we do not have evidence-based or science-based medicine, but rather a commercially distorted marketing-based medicine environment. Former chief-editor of the British Medical Journal, Prof Richard Smith, summed this up in his 2005 article in PLoS Medicine titled "Medical Journals Have Become an Extension of the Marketing Arm of Pharmaceutical Companies".
The medical profession and journals have ethical duties towards scientific truth and the welfare of patients before all else. Big Pharma as capitalistic corporations have a commitment to their bottom line. There is now a solution to this situation - the AllTrials campaign - to bring all research data (anonymised of patients' names) into view for independent analysis. AllTrials has the full backing of the British medical establishment - but needs international support if we are to have a future of Science-Based Medicine to supply the most beneficial and least harmful treatments and most accurate medical knowledge for us all.