Clinical Trials on Vaccines : the Revelations of a Doctor

Meehan MD on the poor science of the recent Danish MMR Autism Study

Published on 6 March 2019, by Jim Meehan, MD

 

The James Lind Library’s Introduction to Fair Tests of Treatments

JLL Book of Essays, About Fair Tests, May 2019

Introduction

At various times in our lives and to varying levels of intensity, we all use, provide or pay for health and social care. As we decide what to do, take, offer or buy, we need evidence that is reliable, robust and trustworthy about different options. Even before James Lind’s experiment comparing possible treatments for scurvy on HMS Salisbury people had recognised that getting this evidence requires strenuous efforts to reduce bias –but that achieving this is often not straightforward. This book of essays from the James Lind Library is our attempt to illustrate some of the challenges encountered and how to overcome them.

We will take you on a journey through the sometimes stormy waters of why treatments need to be tested, rather than being based on assumptions that “it must work” before the treatment has even been tried, or based on impressions after it has been used a few times, through to the need for fair tests comparing alternative treatment options. We will show why genuine uncertainties must be identified and addressed, and how research to find the most effective and appropriate treatments need to build on research to identify the most effective and appropriate methods for doing that research. We will navigate through the reasons why comparisons need to be fair at the outset, and then kept fair as the treatments being tested are given;outcomes are measured;and results are analysed, reported, and combined in systematic reviews of all the relevant, trustworthy evidence.

We have not cluttered the chapters with references to all the source material on which we have drawn. For that level of detail, please follow the links to the fuller essays on the James Lind Library website. Instead, where we know of reviews of methodology research which are relevant to a topic, we have listed these at the end of each chapter.

By the end of the book, we hope that you will recognise how, to bring benefits of research to patients and the public, systematic reviews of fair tests are needed to provide key elements of the knowledge needed to inform decisions about health and social care, while taking into account other important factors, such as values, preferences, needs, resources and priorities. We also hope that, as you finish the book, you will share the sense of enlightenment, education and enjoyment that we have gained from preparing it.

Finally, we dedicate this book to England’s National Institute for Health Research. Without the Institute’s 16-year-long support for the James Lind Initiative, the home of the James Lind Library during that time, neither the Library nor these essays would have been possible. And we also wish to acknowledge the role the Institute plays in recognising the vital contribution of research to the delivery of health and social care that is effective and efficient, and the Institute’s leadership in ensuring that the research itself is effective, efficient and reliable, with minimal waste.

Abstract

1.3 Why treatment comparisons must be fair

Untrustworthy treatment comparisons are those in which biases, or the play of chance, or both result in misleading estimates of the effects of treatments. Fair treatment comparisons avoid biases and reduce the effects of the play of chance.

It is not only failure to test theories about treatments in practice that has caused preventable tragedies. They have also occurred because the tests used to assess the effects of treatments have been unreliable and misleading. In the 1950s, theory and poorly controlled tests yielded unreliable evidence suggesting that diethylstilboestrol (DES) helped pregnant women who had previously had miscarriages and stillbirths. Although fair tests suggested that DES was useless, theory and unreliable evidence, together with aggressive marketing, led to DES being prescribed to millions of pregnant women over the next few decades. The consequences were disastrous for the women and their children, who experienced infertility and cancers as a result. The lesson is that a treatment that has not been reliably shown to be useful should not be promoted.

Problems resulting from inadequate tests of treatments continue to occur. Again, because of unreliable evidence and aggressive marketing, millions of women were persuaded to use hormone replacement therapy (HRT). It was claimed that, not only could it reduce unpleasant menopausal symptoms, but also the chances of having heart attacks and strokes. When these claims were assessed in fair tests, the results showed that in women over 60, far from reducing the risks of heart attacks and strokes, HRT increases the risks of these life-threatening conditions, as well as having other undesirable effects.These examples of the need for fair tests of treatments are a few of many that illustrate how treatments can do more harm than good. Improved general knowledge about fair tests of treatments is needed so that –laced with a healthy dose of scepticism –we can all assess claims about the effects of treatments more critically. That way, we will all become more able to judge which treatments are likely to do more good than harm.

DES DiEthylStilbestrol Resources

Meet the people who lived with defective devices

Implant Files, video published by ICIJ, 25 November 2018

ICIJ listened to hundreds of stories from patients with poorly-functioning medical devices. Here are just five of their testimonies.

Read more about ICIJ implant files investigation.

ICIJfights corruption with the world’s best cross-border watchdog journalism by over 160 investigative reporters in 60+ countries. The home of Offshore Leaks.”

Why join the Implant Files investigation ?

Implant Files, video published by ICIJ, 25 November 2018

Journalists explain why they decided to investigate medical device harm with ICIJ reporters.

Read more about ICIJ implant files investigation.

ICIJfights corruption with the world’s best cross-border watchdog journalism by over 160 investigative reporters in 60+ countries. The home of Offshore Leaks.”

A global investigation into medical device harm

Implant Files, video published by ICIJ, 24 November 2018

Patients around the world have become unwitting test subjects for new medical technology. Often following the trusted advice of their doctors, they have been injured, maimed and killed by poorly-tested implants.

Read more about the their implant files investigation.

ICIJfights corruption with the world’s best cross-border watchdog journalism by over 160 investigative reporters in 60+ countries. The home of Offshore Leaks”.

Major US funders ($$ billions) are pushing for greater clinical trials transparency

Noncommercial US Funders’ Policies on Trial Registration, Access to Summary Results, and Individual Patient Data Availability

2019 Study Key Points

  • Question
    What are the current policies for clinical trial registration, summary results sharing, and individual patient data sharing among the top 10 noncommercial US health research funders?
  • Findings
    In this review study, 6 of 9 (67%) of the top US funders have a publicly available written policy addressing all 3 major trial transparency domains. However, fewer US funders require specific transparency actions in these domains (11%-56%) or monitor compliance with their policies (56%-67%).
  • Meaning
    More work remains to be done to ensure timely implementation and enforcement of clinical trial transparency initiatives to reduce waste and realize public value from clinical research investments.

Abstract

Importance
Incomplete information about existing research is an underlying cause of research waste. National and international initiatives and requirements have been launched to address this issue.

Objectives
To characterize current clinical trial transparency policies among the largest noncommercial US funders and examine whether the policies are concordant with international funders.

Design, Setting, and Participants
This retrospective review of public information used methods developed for documenting funder policies internationally; 2 researchers searched each funder’s website and Google between May and November 2018 to locate trial transparency policies for 10 top US funders. Key informants at each funding organization were contacted by email and given 3 or more weeks to review and confirm or correct the findings. Nonresponders were contacted 2 or more additional times. Descriptive statistics were calculated to summarize the findings. The study was conducted using publicly available policy information with findings confirmed by funder representatives where possible. Participants included top 10 noncommercial US health research funders with the highest reported investment in health research (2013 dollars) who fund clinical trials. Data analysis was conducted from November 6, 2018, to November 23, 2018.

Exposures
Availability of policies addressing each of the 3 key trial transparency domains as specified by the World Health Organization in 2017.

Main Outcomes and Measures
Independent assessment by 2 investigators of availability (yes or no) of a policy addressing registration for trials, sharing of summary results, and individual participant data sharing activities; requirements (yes, no, or supportive statement) of these policies in terms of completeness, timeliness, public access, and provision of additional technical or financial support to meet data sharing requirements; description (yes or no) of internal monitoring for policy adherence.

Results
All 10 funders acknowledged the outreach. One funder who indicated that less than 1% of their research funding goes to clinical trials was removed. Six (67%) of the remaining 9 top US funders have a publicly available written policy for all 3 major trial transparency domains. The most comprehensive trial transparency practice among US funders addresses summary results sharing as follows: 8 of 9 US funders (89%) have a policy, 5 of 9 US funders (56%) require reporting of summary results within 1 year, and 6 of 9 US funders (67%) monitor compliance with their summary results sharing policy. For clinical trial registration, 7 of 9 US funders (78%) have a policy and 5 of 9 US funders (56%) require registration and monitor trial registration to measure adherence to the policy.

Conclusions and Relevance
In this study, overall the proportion of US funders with policies and practices to support trial transparency in this sample was similar or compared favorably with the larger international sample of noncommercial funders recently reported.

 

Unbiased information on medicines : Why is it needed?

Pharmaceutical promotion practices HAI webinar, Oct 2018

Dr Barbara Mintzes (University of Sydney) joins Health Action International for an expert webinar on pharmaceutical promotion practices.

89% of clinical trials run by European universities violate EU regulations, study shows

Compliance with requirement to report results on the EU Clinical Trials Register: cohort study and web resource

Data released today via the BMJ show that thousands of clinical trials conducted in Europe violate EU rules that require results to be published within 12 months. Failure to publish trial results endangers patients, contributes to exploding drug costs, and slows down the discovery of new treatments and cures, transparimed reports.

Abstract

Objectives
To ascertain compliance rates with the European Commission’s requirement that all trials on the EU Clinical Trials Register (EUCTR) post results to the registry within 12 months of completion (final compliance date 21 December 2016); to identify features associated with non-compliance; to rank sponsors by compliance; and to build a tool for live ongoing audit of compliance.

Design
Retrospective cohort study.

Setting
EUCTR.

Participants
7274 of 11 531 trials listed as completed on EUCTR and where results could be established as due.

Main outcome measure
Publication of results on EUCTR.

Results
Of 7274 trials where results were due, 49.5% (95% confidence interval 48.4% to 50.7%) reported results. Trials with a commercial sponsor were substantially more likely to post results than those with a non-commercial sponsor (68.1% v 11.0%, adjusted odds ratio 23.2, 95% confidence interval 19.2 to 28.2); as were trials by a sponsor who conducted a large number of trials (77.9% v 18.4%, adjusted odds ratio 18.4, 15.3 to 22.1). More recent trials were more likely to report results (per year odds ratio 1.05, 95% confidence interval 1.03 to 1.07). Extensive evidence was found of errors, omissions, and contradictory entries in EUCTR data that prevented ascertainment of compliance for some trials.

Conclusions
Compliance with the European Commission requirement for all trials to post results on to the EUCTR within 12 months of completion has been poor, with half of all trials non-compliant. EU registry data commonly contain inconsistencies that might prevent even regulators assessing compliance. Accessible and timely information on the compliance status of each individual trial and sponsor may help to improve reporting rates.

Do we have the proper guard rails for first-in-man clinical trials?

Consider drug efficacy before first-in-human trials

“On 17 January 2016, a healthy man was declared brain-dead after receiving an experimental drug in a first-in-human trial in France. Four of five other subjects receiving the same dose have serious, ongoing neurological complications. Investigations into the trial described many troubling safety practices, such as steep increases in dose levels delivered to sequential subjects without sufficient delays to check for safety.

Ethical review boards must focus on clinical promise as well as safety to hold the first tests of drugs in humans to a higher standard.

Image credit Richard Wilkinson.

The year since has brought intense scrutiny about how the debacle could have been anticipated and prevented. However, another issue is still largely overlooked: the duty to evaluate whether an experimental treatment is promising enough to warrant testing on people.”…

… continue reading Consider drug efficacy before first-in-human trials, by Jonathan Kimmelman and Carole Federico, Nature, 30 January 2017.

The importance of patient reporting of adverse drug reactions

The value of patient reporting to the pharmacovigilance system: a systematic review

2016 Study Abstract

Aims
Current trends in pharmacovigilance systems are veering towards patient involvement in spontaneous reporting of adverse drug reactions (ADRs). The aim of the current systematic review was to identify what is known and what remains unknown with respect to patient reporting to pharmacovigilance systems.

Methods
A systematic literature search was conducted in PubMed, CINAHL, Journals@Ovid and the Cochrane Library. Studies were included if they contained:

  • reviews about patient reporting;
  • evaluation of patient reports to national or supranational pharmacovigilance authorities;
  • a comparison between patient and healthcare professional (HCP) reports submitted to pharmacovigilance authorities;
  • and surveys of patient experiences, opinions and awareness about reporting ADRs.

The methodological quality of the studies was assessed according to principles of Grading of Recommendations, Assessment, Development and Evaluations (GRADE).

The value of patient reporting to the pharmacovigilance system: a systematic review, wiley online library, DOI: 10.1111/bcp.13098, 12 October 2016.

Image credit lac-bac.

Thank you Malak Abou Taam for your tweet.

Results
A total of thirty four studies were included. Five of the studies were reviews (two of which systematic reviews), fourteen retrospective observational studies, nine surveys and six applied mixed research methods. Patient reporting has the advantages of bringing novel information about ADRs. It provides a more detailed description of ADRs, and reports about different drugs and system organ classes when compared with HCP reporting. In addition, patients describe the severity and impact of ADRs on daily life, complementing information derived from HCPs. Patient reporting is relatively rare in most countries.

Conclusions
Patient reporting adds new information, and perspective about ADRs in a way otherwise unavailable. This can contribute to better decision-making processes in regulatory activities. The present review identified gaps in knowledge that should be addressed to improve our understanding of the full potential and drawbacks of patient reporting.