Evaluation of clinical trial registration, reporting and publication rates for new drugs

How pharma keeps a trove of drug trials out of public view

image of clinical-trial-capsules
A third of the clinical trial results that federal regulators reviewed to approve drugs made by large pharmaceutical companies in 2012 were never publicly reported, according to a new study that grades companies on their transparency. clinical trial capsules by Esther Dyson.

2015 Study Abstract

To evaluate clinical trial registration, reporting and publication rates for new drugs by:

  1. legal requirements and
  2. the ethical standard that all human subjects research should be publicly accessible to contribute to generalisable knowledge.

Cross-sectional analysis of all clinical trials submitted to the Food and Drug Administration (FDA) for drugs approved in 2012, sponsored by large biopharmaceutical companies.

Data sources
Information from Drugs@FDA, ClinicalTrials.gov, MEDLINE-indexed journals and drug company communications.

Main outcome measures
Clinical trial registration and results reporting in ClinicalTrials.gov, publication in the medical literature, and compliance with the 2007 FDA Amendments Acts (FDAAA), analysed on the drug level.

The FDA approved 15 drugs sponsored by 10 large companies in 2012. We identified 318 relevant trials involving 99 599 research participants. Per drug, a median of 57% (IQR 32–83%) of trials were registered, 20% (IQR 12–28%) reported results in ClinicalTrials.gov, 56% (IQR 41–83%) were published, and 65% (IQR 41–83%) were either published or reported results. Almost half of all reviewed drugs had at least one undisclosed phase II or III trial. Per drug, a median of 17% (IQR 8–20%) of trials supporting FDA approvals were subject to FDAAA mandated public disclosure; of these, a median of 67% (IQR 0–100%) were FDAAA-compliant. 68% of research participants (67 629 of 99 599) participated in FDAAA-subject trials, with 51% (33 405 of 67 629) enrolled in non-compliant trials. Transparency varied widely among companies.

Trial disclosures for new drugs remain below legal and ethics standards, with wide variation in practices among drugs and their sponsors. Best practices are emerging. 2 of our 10 reviewed companies disclosed all trials and complied with legal disclosure requirements for their 2012 approved drugs. Ranking new drugs on transparency criteria may improve compliance with legal and ethics standards and the quality of medical knowledge.

Sources and more information

Overuse of medical care, overdiagnosis and overtreatment questioned

Astounding Number of Medical Procedures Have No Benefit, Even Harm

A concerning new review published in the Journal of the American Medical Association online ahead of print on the topic of overuse of medical care, i.e., health care for which “risk of harm exceeds its potential for benefit,” finds that many commonly employed medical procedures, to which millions are subjected to each year, are based on questionable if not also, in some cases, non-existent evidence.

2015 Study Abstract

Overuse of medical care, consisting primarily of overdiagnosis and overtreatment, is a common clinical problem.

To identify and highlight articles published in 2014 that are most likely to influence medical overuse, organized into the categories of overdiagnosis, overtreatment, and methods to avoid overuse, and to review these articles and interpret them for their importance to clinical medicine.

A structured review of English-language articles in PubMed published in 2014 and a review of tables of contents of relevant journals to identify potential articles that related to medical overuse in adults.

We reviewed 910 articles, of which 440 addressed medical overuse. Of these, 104 were deemed most relevant based on the presentation of original data, quality of methods, magnitude of clinical effect, and number of patients potentially affected. The 10 most influential articles were selected by author consensus using the same criteria. Findings included

  • lack of benefit for screening pelvic examinations (positive predictive value <5%),
  • carotid artery screening (no reduction in stroke),
  • and thyroid ultrasonography (15-fold increase in thyroid cancer).
  • The harms of cancer screening included
    • unnecessary surgery
    • and complications.
  • Head computed tomography was an overused diagnostic test (clinically significant findings in 4% [7 of 172] of head computed tomographic scans).
  • Overtreatment included
    • acetaminophen for low back pain,
    • perioperative aspirin use,
    • medications to increase high-density lipoprotein cholesterol level,
    • stenting for renal artery stenosis,
    • and prolonged opioid use after surgery (use >90 days in 3% [1229 of 39 140] of patients).

Many common medical practices should be reconsidered. It is anticipated that our review will promote reflection on these 10 articles and lead to questioning of other non-evidence-based practices.

Sources and more information
  • Update on Medical Practices That Should Be Questioned in 2015, JAMA Internal Medicine, doi:10.1001/jamainternmed.2015.5614, November 09, 2015.
  • Astounding Number of Medical Procedures Have No Benefit, Even Harm, greenmedinfo, November 10th 2015.

Exposure to EDCs during Pregnancy and Overweight at 7 Years of Age

Obesogens: An Environmental Link to Obesity

Human-made chemicals appear to trigger obesity, even when they pass from the pregnant mother to her child. Excess weight in children can be a harbinger of Type 2 diabetes later in life. Santa Ana Misc by heacphotos.

2015 Study Abstract

Prenatal exposure to endocrine-disrupting chemicals (EDCs) may induce weight gain and obesity in children, but the obesogenic effects of mixtures have not been studied.

We evaluated the associations between pre- and perinatal biomarker concentrations of 27 EDCs and child weight status at 7 years of age.

In pregnant women enrolled in a Spanish birth cohort study between 2004 and 2006, we measured the concentrations of 10 phthalate metabolites, bisphenol A, cadmium, arsenic, and lead in two maternal pregnancy urine samples; 6 organochlorine compounds in maternal pregnancy serum; mercury in cord blood; and 6 polybrominated diphenyl ether congeners in colostrum. Among 470 children at 7 years, body mass index (BMI) z-scores were calculated, and overweight was defined as BMI > 85th percentile. We estimated associations with EDCs in single-pollutant models and applied principal-component analysis (PCA) on the 27 pollutant concentrations.

In single-pollutant models, HCB (hexachlorobenzene), βHCH (β-hexachlorocyclohexane), and polychlorinated biphenyl (PCB) congeners 138 and 180 were associated with increased child BMI z-scores; and HCB, βHCH, PCB-138, and DDE (dichlorodiphenyldichloroethylene) with overweight risk. PCA generated four factors that accounted for 43.4% of the total variance. The organochlorine factor was positively associated with BMI z-scores and with overweight (adjusted RR, tertile 3 vs. 1: 2.59; 95% CI: 1.19, 5.63), and these associations were robust to adjustment for other EDCs. Exposure in the second tertile of the phthalate factor was inversely associated with overweight.

Prenatal exposure to organochlorines was positively associated with overweight at age 7 years in our study population. Other EDCs exposures did not confound this association.

Sources and more information
  • Chemical used in nonstick coatings may cause obesity in region’s kids: study, cincinnati, November 12, 2015.
  • Exposure to Endocrine-Disrupting Chemicals during Pregnancy and Weight at 7 Years of Age: A Multi-pollutant Approach, doi: 10.1289/ehp.1409049, 123(10): 1030–1037, 2015 Oct.
  • Obesogens: An Environmental Link to Obesity, Environ Health Perspectives, doi: 10.1289/ehp.120-a62, 2012 Feb.

DES (Diethylstilbestrol) Resource Guide 1980

National Women’s Health Network, 1980

DES-Guide 1980 cover image
Click image above to download PDF (3.3 MB).

National Women’s Health Network,
Resource Guide 6, 1980

The sixth resource guide of the 1980 series published by the National Women’s Health Network concerns DES (diethylstilbestrol), a synthetic estrogen prescribed to women, usually during pregnancy, from the time of its discovery in 1938 and even after it was banned by the FDA in 1971.

As this guide details, direct exposure to DES increases the risk of breast cancer, while exposure in utero may lead to cancer or physical disabilities.

In addition to documenting the effects of DES, this guide also provides resources and information for mothers and daughters who have been exposed.

More DES DiEthylStilbestrol Resources

Health risks and effects of prenatal exposure to diethylstilbestrol

The Journal of family practice, 1983

DiEthylStilbestrol usage review buttress the need for adequate and rigorous research into the use of drugs in pregnancy and ensure that they do more good than harm before being introduced for consumption.
Strangers in the Rain by indicpeace.

1983 Study Abstract

Patients exposed prenatally to diethylstilbestrol (DES) have been shown to have a number of significant health risks that may be considered in the evaluation of this population. Neoplastic lesions of the cervix and vagina have been observed in a few patients. Increased prevalence of squamous intraepithelial neoplasms has been reported by several large clinical centers, and a recent observation of ovarian neoplasms has been reported. The significance of these observations remains to be substantiated. Anatomic deformities of the cervix, vagina, uterus, and fallopian tubes have been associated with increased pregnancy loss or infertility. The epithelial abnormalities of adenosis and cervical erosion essentially hallmark prenatal exposure to diethylstilbestrol. These changes are in themselves not malignant or premalignant and rarely warrant therapy.

Sources and more information
  • Health risks and effects of prenatal exposure to diethylstilbestrol, The Journal of family practice, NCBI PMID: 6848637, 1983 Jan;16(1):51-4.
More DES DiEthylStilbestrol Resources

Perturbateurs endocriniens: les lobbies nuisent-ils gravement à la santé?

ICI L’EUROPE, avec Stephane Horel, 2015

Une émission présentée par Caroline de Camaret avec Stephane Horel. Production : Isabelle Romero. Vidéo publiée le 11 novembre 2015 par FRANCE 24.

En savoir plus

  • Après le scandale Volkswagen, une nouvelle polémique de santé publique touche l’Europe : les perturbateurs endocriniens. Ces substances chimiques sont présentes dans de nombreux objets de consommation courante : plastiques, résidus de pesticides sur les fruits et légumes, OGM, cosmétiques, lunettes, semelles de chaussures… Ces perturbateurs interagissent avec le système hormonal et seraient responsables de l’augmentation de certains cancers, selon des associations impliquées dans les problèmes de santé liés à l’environnement. L’Union européenne, très en avance sur la détection des substances toxiques, est accusée d’avoir repoussé la réglementation les concernant sous la pression des lobbies.
  • Regardez ces vidéos BPA et pesticides sur notre chaine YouTube.

How do you want to take the DES hormone?

Diethylstilbestrol found in veal meat… a 1980 Germany food scandal

DES-in-veal cartoon
You can choose how you want to take the hormone – via pills, injection or (eating) veal “
Related posts
Related books
More DES DiEthylStilbestrol Resources

The Role of Hox Genes in Female Reproductive Tract Development, Adult Function, and Fertility

DES alteration of HOX gene expression prevent implantation and lead to female infertility.

image of hands
DES alteration of HOX gene expression causes both uterine developmental abnormalities and impaired adult endometrial development that prevent implantation and lead to female infertility. Hands by Andrew Storms.

2015 Study Abstract

HOX genes convey positional identity that leads to the proper partitioning and adult identity of the female reproductive track. Abnormalities in reproductive tract development can be caused by HOX gene mutations or altered HOX gene expression. Diethylstilbestrol (DES) and other endocrine disruptors cause Müllerian defects by changing HOX gene expression. HOX genes are also essential regulators of adult endometrial development. Regulated HOXA10 and HOXA11 expression is necessary for endometrial receptivity; decreased HOXA10 or HOXA11 expression leads to decreased implantation rates. Alternation of HOXA10 and HOXA11 expression has been identified as a mechanism of the decreased implantation associated with endometriosis, polycystic ovarian syndrome, leiomyoma, polyps, adenomyosis, and hydrosalpinx. Alteration of HOX gene expression causes both uterine developmental abnormalities and impaired adult endometrial development that prevent implantation and lead to female infertility.

Sources and more information
  • The Role of Hox Genes in Female Reproductive Tract Development, Adult Function, and Fertility, Cold Spring Harbor perspectives in medicine, NCBI PMID: 26552702, pii: a023002. doi: 10.1101/cshperspect.a023002, 2015 Nov 9.
    Full text perspectivesinmedicine, doi: 10.1101/cshperspect.a023002,
    November 9, 2015.
More DES DiEthylStilbestrol Resources

Trends in Prescription Drug Use among Adults in the United States

Drug overdose epidemic top cause of US injury deaths

image ofprescription-drugs
Drug overdoses have reached epidemic levels in the United States where they are the leading cause of injury deaths, surpassing car accidents and gunshots. More people abuse prescription medication than cocaine, methamphetamine, heroin, MDMA and PCP combined and prescription drug deaths have outpaced those of cocaine and heroin combined since 2002. ep_jhu.

2015 Study Abstract

To evaluate trends in prescription drug use among adults living in the United States.

Design, Setting, and Participants
Temporal trends in prescription drug use were evaluated using nationally representative data from the National Health and Nutrition Examination Survey (NHANES). Participants included 37 959 noninstitutionalized US adults, aged 20 years and older. Seven NHANES cycles were included (1999-2000 to 2011-2012), and the sample size per cycle ranged from 4861 to 6212.

Calendar year, as represented by continuous NHANES cycle.

Main Outcomes and Measures
Within each NHANES cycle, use of prescription drugs in the prior 30 days was assessed overall and by drug class. Temporal trends across cycles were evaluated. Analyses were weighted to represent the US adult population.

Results indicate an increase in overall use of prescription drugs among US adults between 1999-2000 and 2011-2012 with an estimated 51% of US adults reporting use of any prescription drugs in 1999-2000 and an estimated 59% reporting use of any prescription drugs in 2011-2012 (difference, 8% [95% CI, 3.8%-12%]; P for trend <.001). The prevalence of polypharmacy (use of ≥5 prescription drugs) increased from an estimated 8.2% in 1999-2000 to 15% in 2011-2012 (difference, 6.6% [95% CI, 4.4%-8.2%]; P for trend <.001). These trends remained statistically significant with age adjustment. Among the 18 drug classes used by more than 2.5% of the population at any point over the study period, the prevalence of use increased in 11 drug classes including antihyperlipidemic agents, antidepressants, prescription proton-pump inhibitors, and muscle relaxants.

Conclusions and Relevance
In this nationally representative survey, significant increases in overall prescription drug use and polypharmacy were observed. These increases persisted after accounting for changes in the age distribution of the population. The prevalence of prescription drug use increased in the majority of, but not all, drug classes.

Sources and more information
  • Hooked on Pharmaceuticals: Prescription Drug Abuse in America,
    drugwatch, July 29th, 2015.
  • Trends in Prescription Drug Use Among Adults in the United States From 1999-2012, JAMA. 2015;314(17):1818-1830. doi:10.1001/jama.2015.13766, November 3, 2015.
  • Rx for America: Nearly 6 in 10 adults take prescription drugs, study says,
    latimes, November 3, 2015.
  • 46,471: Drug Overdoses Killed More Americans Than Car Crashes or Guns,
    cnsnews, November 5, 2015.
  • Big Pharma pills and heroin responsible for more than half of drug overdoses,
    medicine.news, November 6th, 2015.
  • DEA Announces “360 Strategy” to Address Heroin, Prescription Drugs and Violent Crime, dea, November 10, 2015.

Cancer Prevention and Safer Chemicals: EDC’s Dirty Dozen 1/3

EWG’s Dirty Dozen: Cancer Prevention Edition 1/3, 2015

EWG_DD_CancerTips-1 infographic
EWG’s Dirty Dozen: Cancer Prevention Edition 1/3

Scientists are only beginning to investigate how certain chemicals may interact to contribute to cancer development. But given that we live in a sea of chemicals, it makes sense to begin reducing exposures to ones we know are bad actors.

Here are EWG‘s tips for avoiding 12 harmful chemicals that have now been found to also disrupt cancer-related pathways — known as cancer hallmarks.

Image sources

    ewg research, AUGUST 6, 2015.
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