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.

Financial ties between researchers and drug industry independently associated with positive trial results

Financial ties of principal investigators and randomized controlled trial outcomes: cross sectional study

2017 Study Abstract

Objective
To examine the association between the presence of individual principal investigators’ financial ties to the manufacturer of the study drug and the trial’s outcomes after accounting for source of research funding.

Design
Cross sectional study of randomized controlled trials (RCTs).

Setting
Studies published in “core clinical” journals, as identified by Medline, between 1 January 2013 and 31 December 2013.

Participants
Random sample of RCTs focused on drug efficacy.

Main outcome measure
Association between financial ties of principal investigators and study outcome.

Results
A total of 190 papers describing 195 studies met inclusion criteria. Financial ties between principal investigators and the pharmaceutical industry were present in 132 (67.7%) studies. Of 397 principal investigators, 231 (58%) had financial ties and 166 (42%) did not. Of all principal investigators, 156 (39%) reported advisor/consultancy payments, 81 (20%) reported speakers’ fees, 81 (20%) reported unspecified financial ties, 52 (13%) reported honorariums, 52 (13%) reported employee relationships, 52 (13%) reported travel fees, 41 (10%) reported stock ownership, and 20 (5%) reported having a patent related to the study drug. The prevalence of financial ties of principal investigators was 76% (103/136) among positive studies and 49% (29/59) among negative studies. In unadjusted analyses, the presence of a financial tie was associated with a positive study outcome (odds ratio 3.23, 95% confidence interval 1.7 to 6.1). In the primary multivariate analysis, a financial tie was significantly associated with positive RCT outcome after adjustment for the study funding source (odds ratio 3.57 (1.7 to 7.7). The secondary analysis controlled for additional RCT characteristics such as study phase, sample size, country of first authors, specialty, trial registration, study design, type of analysis, comparator, and outcome measure. These characteristics did not appreciably affect the relation between financial ties and study outcomes (odds ratio 3.37, 1.4 to 7.9).

Conclusions
Financial ties of principal investigators were independently associated with positive clinical trial results. These findings may be suggestive of bias in the evidence base.

Full study
dx.doi.org/10.1136/bmj.i6770 published 17 January 2017 by The BMJ.

Who is not sharing their clinical trials result?

Nearly half of all trials run by major sponsors in past decade are unpublished

Clinical trials are the best way we have of testing whether a medicine is safe and effective. When trials remain unreported, this means that patients and doctors don’t have the full information about the benefits and risks of treatments.

Trials registered on ClinicalTrials.gov should share results on the site shortly after completing, or publish in a journal. But many organisations fail to report the results of clinical trials. TrialsTracker, a new automated service launched to shine a spotlight on drug companies and universities, found that nearly half of all trials run by major sponsors in the past 10 years were missing results.

For example, the drug company Sanofi has failed to publish results for almost two thirds of the clinical trials it has conducted in the past decade.

Nearly half of all trials run by major sponsors in past decade are unpublished, BMJ 5955, 04 November 2016.

Explore trials tracker data (last updated October 2016) to see the universities, government bodies and pharmaceutical companies that aren’t sharing their clinical trial results.

Synthetic Hormone Given to Healthy Teenage Girls

DES Action Australia – Tall Girls, Today Tonight, 1998

Video published on 24 September 2016 by DES Action Australia.

DES and Quest to Manipulate Height
DES DiEthylStilbestrol Resources

Medical Science Editors, Publishers, Impact Factors, and Reprint Income

Is much of the clinical research that is published still believable?

Editors under Pressure—Avoiding Conflicts

Editors would like to imagine they are simply gatekeepers who facilitate the interaction between authors who wish to impart information and people who want to read it. In fact, they are subject to a raft of external pressures that interfere with this core task. Coauthors are prone to disputes with each other and with reviewers; rejected authors may protest; readers may be dissatisfied; institutions may react inadequately to editors’ concerns about probity; editorial freedom may be compromised by the demands of the learned society that owns the journal; and a commercial publisher might exert subtle—or unsubtle—pressure to increase profitability. All of these distractions increase the possibility of competing interests corrupting the editorial process.

Influence of the Impact Factor

Editors, Publishers, Impact Factors, and Reprint Income, PLoS Medicine, PMC2964337, Oct 26 2010.

Added to this toxic mixture is the impact factor (IF). Just as many clinicians claim that contacts by pharmaceutical company representatives do not affect their prescribing behaviour, so editors are likely to deny that thoughts of a rising IF might influence their acceptance rates. In their paper published this week in PLoS Medicine, Andreas Lundh and colleagues analysed randomised controlled trials published in six high-impact general medical journals during two time periods a decade apart; they calculated the putative fall in IF that would have occurred had publication been denied to papers that were commercially sponsored.

Unsurprisingly, they found the expected association, since IF depends in turn on recent citation rates, and a body of literature shows that industry-sponsored trials attract more citations than those funded by a nonprofit source. There are reasons: for example, randomised controlled trials and meta-analyses are cited more frequently than clinical studies with less-rigorous design, regardless of funding, and high-impact journals are likely to attract the former. There is “gamesmanship,” with commercial sponsors and publishing companies skilled at obtaining publicity in the mass media, a known stimulant for citations. Only slightly dubious is the habit of commercial companies disseminating papers favourable to their product to individual clinicians at conferences or through sponsorship of review papers—themselves a potent accelerator of IF. More culpable is the fact that studies showing positive outcomes for a drug or device under consideration are more likely to be published than “negative” studies; editors are partly to blame for this but so are commercial sponsors, whose methodologically well-conducted studies with unfavourable results tended not to see the light of day, at least in the pretrial registration era.

Lundh and colleagues do not claim that their findings demonstrate that editors’ judgment on acceptance or rejection is influenced by the paper’s predicted effect on IF. Nonetheless, I have heard editors support a paper at a selection meeting by stating that it is likely to be well cited.

Publishers’ Profits and Sponsored Studies

More intriguingly, the second aim of their study was to investigate the possible financial benefits to publishers of the journals they investigated. Their attempted method was to seek data on income from advertisements, reprints, and industry-supported supplements as a percentage of total income. The editors of the two UK-based journals,BMJ and The Lancet, provided the data. The editors of JAMA and The New England Journal of Medicine (NEJM)declined, as did the publisher of Annals of Internal Medicine. The owners of the latter confirmed the proxy data obtained from the US Internal Revenue Service but the publishers of the former two journals, the American Medical Association and the Massachusetts Medical Society, did not respond.

Again, the authors cannot infer the intentions of their nonrespondent editors. Editors are proud of their independence but independence goes only as far as an owner permits, as we know from the sorry history of dismissed editors of NEJM and the Canadian Medical Association Journal, amongst others.

Journals as Leaders: A Paradox

In many ways, JAMA has led the way in promoting publishing integrity—including its call for independent statistical analysis of submitted industry-sponsored trials and its publication of best practice recommendations for professional medical associations. The authors of the latter paper, who include the journal’s editor-in-chief, state:

“Professional medical associations have a duty to bring to their members the best scientific evidence on the efficacy and suitability of drugs and devices. These efforts must be separate from and not affected by industry promotions.”

It is a paradox that the professional medical association that owns JAMA was less than open and transparent with Lundh and colleagues about potential financial conflicts (such as their income from industry sources) as they expect their authors to be.

Stronger Guidance Needed

The various bodies that advise editors may need to strengthen their guidance. The Council of Science Editors’ White Paper on Promoting Integrity in Scientific Journal Publication includes as a potential conflict for editors “employment by an organisation that would obtain some advantage from a favourable product-related publication.” The International Committee of Medical Journal Editors (ICMJE) states that editors who make the final decisions about manuscripts must have no “personal, professional or financial involvement in any of the issues they might judge.” The Committee on Publication Ethics (COPE) code of conduct for editors requires them to prevent business needs from compromising important intellectual standards. None of these organisations comment on the potential conflicts that might arise when a journal or publisher receives a substantial proportion of its income from reprints (23%, Massachusetts Medical Society; 41%, The Lancet; 53%, American Medical Association).

Journal editors have expended much time and effort in teasing out how to handle authors’ and reviewers’ competing interests. They need now to concentrate on their own and those of their employers, lest we reach the dismal scenario described by Marcia Angell:

“it is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines. I take no pleasure in this conclusion, which I reached slowly and reluctantly over my two decades as an editor of The New England Journal of Medicine

Women and Health Research

Ethical and Legal Issues of Including Women in Clinical Studies, Volume 1, 1994

Women-and-Health-Research
Appendix C includes a DES case study

In the nineteenth century some scientists argued that women should not be educated because thinking would use energy needed by the uterus for reproduction. The proof? Educated women had a lower birth rate. Today’s researchers can only shake their heads at such reasoning. Yet professional journals and the popular press are increasingly criticizing medical research for ignoring women’s health issues.

Women and Health Research examines the facts behind the public’s perceptions about women participating as subjects in medical research. With the goal of increasing researchers’ awareness of this important topic, the book explores issues related to maintaining justice (in its ethical sense) in clinical studies.

Leading experts present general principles for the ethical conduct of research on women–principles that are especially important in the light of recent changes in federal policy on the inclusion of women in clinical research.

Women and Health Research documents the historical shift from a paternalistic approach by researchers toward women and a disproportionate reliance on certain groups for research to one that emphasizes proper access for women as subjects in clinical studies in order to ensure that women receive the benefits of research.

The book addresses present-day challenges to equity in four areas:

  • Scientific–Do practical aspects of scientific research work at cross-purposes to gender equity? Focusing on drug trials, the authors identify rationales for excluding people from research based on demographics.
  • Social and Ethical–The authors offer compelling discussions on subjectivity in science, the evidence for male bias, and issues related to race and ethnicity, as well as the recruitment, retention, and protection of research participants.
  • Legal–Women and Health Research reviews federal research policies that affect the inclusion of women and evaluates the basis for researchers’ fears about liability, citing court cases. Appendix C includes a DES case study.
  • Risk–The authors focus on risks to reproduction and offspring in clinical drug trials, exploring how risks can be identified for study participants, who should make the assessment of risk and benefit for participation in a clinical study, and how legal implications could be addressed.

This landmark study will be of immediate use to the research community, policymakers, women’s health advocates, attorneys, and individuals.

DES DiEthylStilbestrol Resources

Big Pharma’s Manipulation and Influence

Truth in Media, 4 Part Series, on Big Pharma Manipulation of Healthcare

Ben Swann Truth in Media – Original Air Date: June-July, 2016.

All 4 parts of Ben Swann’s Truth in Media series about Big Pharma.

More Information

  • When it comes to providing transparency and following proper procedure in protecting the health of the American people:
    • where does the FDA stand?
    • has the FDA maintained its integrity in maintaining oversight of drug companies?
    • is the FDA doing its job to the best of its ability in assuring that our medicines have been rigorously tested?
    • is the FDA making sure that drugs found to be dangerous are assigned proper warnings or removed from the market?
  • New Truth In Media Episodes: Confronting Big Pharma’s Manipulation, Influenc, Truth In Media, Jun 7,, 2016.
More Videos

How Big Pharma rakes in Profits from Deadly Drugs

How the pharmaceutical industry avoids accountability with ‘off label’ drugs

Ben Swann‘s channel, 6 July 2016.

Episode 4 of 4 in Truth in Media series on Big Pharma manipulation of healthcare.

More Information

  • The fourth episode of this serie, How Big Pharma Uses Off-Label Drugs, illustrates how pharmaceutical companies have made massive profits in spite of being ordered to pay enormous settlements related to harmful side effects of certain drugs.
  • How Big Pharma Avoids Accountability With ‘Off Label’ Drugs, Truth In Media, July 8, 2016.
More Videos

Big Pharma Manipulates Physicians and Corrupts “Best Practices”

Pharmaceutical companies have relationships with the regulatory agencies, and then they also heavily influence the education the physicians are getting

Ben Swann‘s channel, 29 Jun 2016.

Episode 3 of 4 in Truth in Media series on Big Pharma manipulation of healthcare.

More Information

  • The third episode of this serie, How Big Pharma Manipulates Physicians and Corrupts “Best Practices,” discusses how companies in the pharmaceutical industry influence doctors’ “best practices” as well as offer funding for research and court physicians and their staff in hopes of gaining loyalty.
  • How Big Pharma Manipulates Physicians and Corrupts ‘Best Practices’, Truth In Media, Jun 29, 2016.
More Videos