Drugs stalled at FDA far more likely to have unpublished trials than licensed ones: 46% vs 10%

Nonpublication of Trial Results for New Neurological Drugs: A Systematic Review

May 2017 Study Abstract

To evaluate nonpublication rates among trials of new successful and unsuccessful neurological drugs – A Systematic Review.

‘Licensed’ drugs consisted of all novel agents receiving FDA licensure 2005 to 2012 inclusive in seven neurological disorders. ‘Stalled’ drugs included all experimental agents tested in the same domains that had at least one completed phase III trial in the same timeframe but failed to receive FDA approval. Trials of these drugs were included in our sample if their primary outcome collection occurred before October 1, 2010. We determined the publication status of eligible trials using searches of clinicaltrials.gov, Google Scholar, PubMed, Embase, sponsor websites, and direct electronic query of trial contacts and sponsors. The primary outcome was time to journal publication (or results reporting in other media) after study completion.

The adjusted hazard ratio for publication was 1.79 (95% confidence interval 1.20 to 2.67) in favour of licensed drugs. Based on the criteria for nonpublication in this report, 14,092 and 33,882 volunteers participated in unpublished trials of licensed and stalled neurological drugs, respectively. Result data were not publicly available in any form for 10% (16/163) and 46% (94/203) of trials of licensed and stalled drugs, respectively.

Results of trials for stalled drugs are heavily underreported. This deprives research and care communities of evidence about pathophysiology, drug class effects, and the value of surrogate endpoints in trials.

Nearly one-third of new drugs have safety concerns after FDA approval

Postmarket Safety Events Among Novel Therapeutics Approved by the US Food and Drug Administration Between 2001 and 2010

How often are safety concerns raised about a drug after it’s been approved by the FDA?.

Nicholas Downing, MD, of the Department of Medicine at Brigham and Women’s Hospital, and colleagues have found that for drugs approved between 2001 and 2010, nearly 1 in 3 had a postmarket safety event.

The team defines postmarket safety events as those that lead to either withdrawal from the market due to safety concerns, a boxed warning or FDA issuance of a safety communication.

They found that of 222 novel therapeutics the FDA approved during this time period, three were withdrawn, 61 received boxed warnings and 59 elicited safety communications.

Key Points

Are characteristics of novel therapeutics known at the time of US Food and Drug Administration (FDA) approval associated with postmarket safety events, including withdrawal, boxed warnings, and safety communications?

Among 222 novel therapeutics approved by the FDA from 2001 through 2010, 71 (32.0%) were affected by a postmarket safety event. Postmarket safety events were more frequent among biologics, therapeutics indicated for the treatment of psychiatric disease, those receiving accelerated approval, and those with near–regulatory deadline approval.

Postmarket safety events are common after FDA approval, highlighting the importance of continuous monitoring of the safety of novel therapeutics throughout their life cycle.

2017 Study Abstract

Postmarket safety events of novel pharmaceuticals and biologics occur when new safety risks are identified after initial regulatory approval of these therapeutics. These safety events can change how novel therapeutics are used in clinical practice and inform patient and clinician decision making.

To characterize the frequency of postmarket safety events among novel therapeutics approved by the US Food and Drug Administration (FDA), and to examine whether any novel therapeutic characteristics known at the time of FDA approval were associated with increased risk.

Design and Setting
Cohort study of all novel therapeutics approved by the FDA between January 1, 2001, and December 31, 2010, followed up through February 28, 2017.

Novel therapeutic characteristics known at the time of FDA approval, including drug class, therapeutic area, priority review, accelerated approval, orphan status, near–regulatory deadline approval, and regulatory review time.

Main Outcomes and Measures
A composite of

  1. withdrawals due to safety concerns,
  2. FDA issuance of incremental boxed warnings added in the postmarket period,
  3. and FDA issuance of safety communications.

From 2001 through 2010, the FDA approved 222 novel therapeutics (183 pharmaceuticals and 39 biologics). There were 123 new postmarket safety events (3 withdrawals, 61 boxed warnings, and 59 safety communications) during a median follow-up period of 11.7 years (interquartile range [IQR], 8.7-13.8 years), affecting 71 (32.0%) of the novel therapeutics. The median time from approval to first postmarket safety event was 4.2 years (IQR, 2.5-6.0 years), and the proportion of novel therapeutics affected by a postmarket safety event at 10 years was 30.8% (95% CI, 25.1%-37.5%). In multivariable analysis, postmarket safety events were statistically significantly more frequent among biologics (incidence rate ratio [IRR] = 1.93; 95% CI, 1.06-3.52; P = .03), therapeutics indicated for the treatment of psychiatric disease (IRR = 3.78; 95% CI, 1.77-8.06; P < .001), those receiving accelerated approval (IRR = 2.20; 95% CI, 1.15-4.21; P = .02), and those with near–regulatory deadline approval (IRR = 1.90; 95% CI, 1.19-3.05; P = .008); events were statistically significantly less frequent among those with regulatory review times less than 200 days (IRR = 0.46; 95% CI, 0.24-0.87; P = .02).

Conclusions and Relevance
Among 222 novel therapeutics approved by the FDA from 2001 through 2010, 32% were affected by a postmarket safety event. Biologics, psychiatric therapeutics, and accelerated and near–regulatory deadline approval were statistically significantly associated with higher rates of events, highlighting the need for continuous monitoring of the safety of novel therapeutics throughout their life cycle.

Association between physicians’ interaction with pharmaceutical companies and their clinical practices

A systematic review and meta-analysis, 2017


Pharmaceutical company representatives likely influence the prescribing habits and professional behaviors of physicians. The objective of this study was to systematically review the association between physicians’ interactions with pharmaceutical companies and their clinical practices.

We used the standard systematic review methodology. Observational and experimental study designs examining any type of targeted interaction between practicing physicians and pharmaceutical companies were eligible. The search strategy included a search of MEDLINE and EMBASE databases up to July 2016. Two reviewers selected studies, abstracted data, and assessed risk of bias in duplicate and independently. We assessed the quality of evidence using the GRADE approach.

Twenty articles reporting on 19 studies met our inclusion criteria. All of these studies were conducted in high-income countries and examined different types of interactions, including detailing, industry-funded continuing medical education, and receiving free gifts. While all included studies assessed prescribing behaviors, four studies also assessed financial outcomes, one assessed physicians’ knowledge, and one assessed their beliefs. None of the studies assessed clinical outcomes. Out of the 19 studies, 15 found a consistent association between interactions promoting a medication, and inappropriately increased prescribing rates, lower prescribing quality, and/or increased prescribing costs. The remaining four studies found both associations and lack of significant associations for the different types of exposures and drugs examined in the studies. A meta-analysis of six of these studies found a statistically significant association between exposure and physicians’ prescribing behaviors (OR = 2.52; 95% CI 1.82–3.50). The quality of evidence was downgraded to moderate for risk of bias and inconsistency. Sensitivity analysis excluding studies at high risk of bias did not substantially change these results. A subgroup analysis did not find a difference by type of exposure.

There is moderate quality evidence that physicians’ interactions with pharmaceutical companies are associated with their prescribing patterns and quality.

The potential downsides of long-term analgesic use

The Ibuprofen Risks You Need to Know

“Painkillers you can get without a prescription—like acetaminophen, as well as ibuprofen, naproxen, and other so-called non steroidal anti-inflammatory drugs (NSAIDs)—are generally pretty safe. That’s why they are available over the counter to relieve mild-to-moderate pain from headaches, sore muscles and achy joints.

But if they’re used more frequently, or over long periods of time, they may pose dangers to the heart, kidneys, bone and even hearing.”

… continue reading The Ibuprofen Risks You Need to Know on TIME Health, Apr 20, 2017. Image credit andrea.

Could Birth Control Pills Make You Feel Bad ?

It’s Not in Your Head: Your Birth Control Pills Might Be Making You Feel Crappy

A new study found that oral contraceptives lowered women’s quality of life. The average decrease was small, but for certain women the effects could be significant, researchers say.

2017 Study Abstract

To determine whether there is a causal effect of oral contraceptive (OC) treatment on general well-being and depressed mood in healthy women.

Double-blind, randomized, and placebo-controlled trial.

University hospital.

Three hundred and forty healthy women aged 18–35 years randomized to treatment, of whom 332 completed the data collection at follow-up evaluation.

A combined OC (150 μg levonorgestrel and 30 μg ethinylestradiol) or placebo for 3 months of treatment.

Main Outcome Measure(s)
Primary outcome measures: global score of Psychological General Well-Being Index (PGWBI) and the Beck Depression Inventory (BDI); secondary outcome measures: six separate dimensions of the PGWBI.

A responsible physician should warn their patients that some women generally don’t feel well on the pill and, if this turns out to be the case, alternatives are available.

The OC treatment statistically significantly decreased general well-being compared with placebo −4.12 (95% CI, −7.18 to −1.06). Furthermore, OC decreased the following PGWBI dimensions compared with placebo: positive well-being −3.90 (95% CI, −7.78 to −0.01), self-control −6.63 (95% CI, −11.20 to −2.06), and vitality −6.84 (95% CI, −10.80 to −2.88). The effect of OC on depressive symptoms and on the PGWBI dimension depressed mood were not statistically significant.

This study demonstrates a statistically significant reduction in general well-being by a first-choice OC in comparison with placebo in healthy women. We found no statistically significant effects on depressive symptoms. A reduction in general well-being should be of clinical importance.

Sources and Press Releases
  • A first-choice combined oral contraceptive influences general well-being in healthy women: a double-blind, randomized, placebo-controlled trial, Fertility and Sterility, dx.doi.org/10.1016/j.fertnstert.2017.02.120, April 19, 2017.
  • It’s Not in Your Head: Your Birth Control Pills Might Be Making You Feel Crappy, health, April 20, 2017.
  • The Pill image credit Sarah C.

Antidepressant Use in Pregnancy and Preterm Birth, ASD, ADHD in Offspring

Is first-trimester maternal antidepressant use related to offspring birth problems, neurodevelopmental problems, or both?

1. Association Between Maternal Use of SSRI Medications and Autism in Their Children

In the February 2016 issue of JAMA Pediatrics, Boukhris and colleagues reported that in utero exposure to selective serotonin reuptake inhibitors (SSRIs) was associated with a significantly increased risk for autism. The authors examined all pregnancies from 1998 to 2009 in the Québec Pregnancy/Children Cohort database that resulted in children with autism spectrum disorder (ASD) as the primary outcome. Among 145 456 full-term infants included in the analysis, 1054 children were diagnosed with ASD by the mean age of 6.2 years (SD, 3.2 years) at follow-up, including 1008 cases of ASD among 140 732 children (0.72%) who were not exposed to antidepressants, and 31 cases of ASD among the 2532 (1.2%) children who were exposed to SSRIs during the second or third trimester. Based on these results, the authors concluded that second- or third-trimester exposure to SSRIs was associated with increased risk for ASD (adjusted hazard ratio, 1.87; 95% CI, 1.15-3.04).

2017 Study Abstract

The association between the use of antidepressants during gestation and the risk of autism spectrum disorder (ASD) in children is still controversial. The etiology of ASD remains unclear, although studies have implicated genetic predispositions, environmental risk factors, and maternal depression.

To examine the risk of ASD in children associated with antidepressant use during pregnancy according to trimester of exposure and taking into account maternal depression.

Design, Setting, and Participants
We conducted a register-based study of an ongoing population-based cohort, the Québec Pregnancy/Children Cohort, which includes data on all pregnancies and children in Québec from January 1, 1998, to December 31, 2009. A total of 145 456 singleton full-term infants born alive and whose mothers were covered by the Régie de l’assurance maladie du Québec drug plan for at least 12 months before and during pregnancy were included. Data analysis was conducted from October 1, 2014, to June 30, 2015.

Antidepressant exposure during pregnancy was defined according to trimester and specific antidepressant classes.

Main Outcomes and Measures
Children with ASD were defined as those with at least 1 diagnosis of ASD between date of birth and last date of follow-up. Cox proportional hazards regression models were used to estimate crude and adjusted hazard ratios with 95% CIs.

During 904 035.50 person-years of follow-up, 1054 children (0.7%) were diagnosed with ASD; boys with ASD outnumbered girls by a ratio of about 4:1. The mean (SD) age of children at the end of follow-up was 6.24 (3.19) years. Adjusting for potential confounders, use of antidepressants during the second and/or third trimester was associated with the risk of ASD (31 exposed infants; adjusted hazard ratio, 1.87; 95% CI, 1.15-3.04). Use of selective serotonin reuptake inhibitors during the second and/or third trimester was significantly associated with an increased risk of ASD (22 exposed infants; adjusted hazard ratio, 2.17; 95% CI, 1.20-3.93). The risk was persistent even after taking into account maternal history of depression (29 exposed infants; adjusted hazard ratio, 1.75; 95% CI, 1.03-2.97).

Conclusions and Relevance
Use of antidepressants, specifically selective serotonin reuptake inhibitors, during the second and/or third trimester increases the risk of ASD in children, even after considering maternal depression. Further research is needed to specifically assess the risk of ASD associated with antidepressant types and dosages during pregnancy.

2. Associations of Maternal Antidepressant Use During the First Trimester of Pregnancy With Preterm Birth, Small for Gestational Age, Autism Spectrum Disorder, and Attention-Deficit/Hyperactivity Disorder in Offspring

Key Points

In this retrospect cohort study of 1 580 629 Swedish offspring using multiple statistical and methodical approaches to adjust for confounding, first-trimester antidepressant exposure was significantly associated with preterm birth (odds ratio, 1.3 in a sibling comparison analysis) but not with risk of being born small for gestational age or later autism spectrum disorder or attention-deficit/hyperactivity disorder.

After accounting for confounding factors, first-trimester antidepressant exposure, compared with no exposure, was associated with a small increased risk of preterm birth but no increased risk of small for gestational age, autism spectrum disorder, or attention-deficit/hyperactivity disorder.

2017 Abstract

Prenatal antidepressant exposure has been associated with adverse outcomes. Previous studies, however, may not have adequately accounted for confounding.

To evaluate alternative hypotheses for associations between first-trimester antidepressant exposure and birth and neurodevelopmental problems.

Design, Setting, and Participants
This retrospective cohort study included Swedish offspring born between 1996 and 2012 and followed up through 2013 or censored by death or emigration. Analyses controlling for pregnancy, maternal and paternal covariates, as well as sibling comparisons, timing of exposure comparisons, and paternal comparisons, were used to examine the associations.

Maternal self-reported first-trimester antidepressant use and first-trimester antidepressant dispensations.

Main Outcomes and Measures
Preterm birth (< 37 gestational weeks), small for gestational age (birth weight < 2 SDs below the mean for gestational age), and first inpatient or outpatient clinical diagnosis of autism spectrum disorder and attention-deficit/hyperactivity disorder in offspring.

Among 1 580 629 offspring (mean gestational age, 279 days; 48.6% female; 1.4% [n = 22 544] with maternal first-trimester self-reported antidepressant use) born to 943 776 mothers (mean age at childbirth, 30 years), 6.98% of exposed vs 4.78% of unexposed offspring were preterm, 2.54% of exposed vs 2.19% of unexposed were small for gestational age, 5.28% of exposed vs 2.14% of unexposed were diagnosed with autism spectrum disorder by age 15 years, and 12.63% of exposed vs 5.46% of unexposed were diagnosed with attention-deficit/hyperactivity disorder by age 15 years. At the population level, first-trimester exposure was associated with all outcomes compared with unexposed offspring (preterm birth odds ratio [OR], 1.47 [95% CI, 1.40-1.55]; small for gestational age OR, 1.15 [95% CI, 1.06-1.25]; autism spectrum disorder hazard ratio [HR], 2.02 [95% CI, 1.80-2.26]; attention-deficit/hyperactivity disorder HR, 2.21 [95% CI, 2.04-2.39]). However, in models that compared siblings while adjusting for pregnancy, maternal, and paternal traits, first-trimester antidepressant exposure was associated with preterm birth (OR, 1.34 [95% CI, 1.18-1.52]) but not with small for gestational age (OR, 1.01 [95% CI, 0.81-1.25]), autism spectrum disorder (HR, 0.83 [95% CI, 0.62-1.13]), or attention-deficit/hyperactivity disorder (HR, 0.99 [95% CI, 0.79-1.25]). Results from analyses assessing associations with maternal dispensations before pregnancy and with paternal first-trimester dispensations were consistent with findings from the sibling comparisons.

Conclusions and Relevance
Among offspring born in Sweden, after accounting for confounding factors, first-trimester exposure to antidepressants, compared with no exposure, was associated with a small increased risk of preterm birth but no increased risk of small for gestational age, autism spectrum disorder, or attention-deficit/hyperactivity disorder.

Image credit Jamie Campbell.

Short-term use of oral corticosteroids linked to serious health problems

Common drugs, uncommon risks? Higher rate of serious problems after short-term steroid use

Millions of times a year, Americans get prescriptions for a week’s worth of steroid pills, hoping to ease a backache or quell a nagging cough or allergy symptoms.

new study from the University of Michigan suggests that we need to pay more attention to the potential side effects of oral corticosteroids, even for short term use.

People taking the pills were more likely to

  • break a bone,
  • have a potentially dangerous blood clot
  • or suffer a life-threatening bout of sepsis in the months after their treatment,

compared with similar adults who didn’t use short-term steroids…

2017 Study Abstract

To determine the frequency of prescriptions for short term use of oral corticosteroids, and adverse events (sepsis, venous thromboembolism, fractures) associated with their use.

Retrospective cohort study and self controlled case series.

Nationwide dataset of private insurance claims.

Adults aged 18 to 64 years who were continuously enrolled from 2012 to 2014.

Main outcome measures
Rates of short term use of oral corticosteroids defined as less than 30 days duration. Incidence rates of adverse events in corticosteroid users and non-users. Incidence rate ratios for adverse events within 30 day and 31-90 day risk periods after drug initiation.

Of 1 548 945 adults, 327 452 (21.1%) received at least one outpatient prescription for short term use of oral corticosteroids over the three year period. Use was more frequent among older patients, women, and white adults, with significant regional variation (all P<0.001). The most common indications for use were upper respiratory tract infections, spinal conditions, and allergies. Prescriptions were provided by a diverse range of specialties. Within 30 days of drug initiation, there was an increase in rates of sepsis (incidence rate ratio 5.30, 95% confidence interval 3.80 to 7.41), venous thromboembolism (3.33, 2.78 to 3.99), and fracture (1.87, 1.69 to 2.07), which diminished over the subsequent 31-90 days. The increased risk persisted at prednisone equivalent doses of less than 20 mg/day (incidence rate ratio 4.02 for sepsis, 3.61 for venous thromboembolism, and 1.83 for fracture; all P<0.001).

One in five American adults in a commercially insured plan were given prescriptions for short term use of oral corticosteroids during a three year period, with an associated increased risk of adverse events.

Sources and Press Releases
  • Short term use of oral corticosteroids and related harms among adults in the United States: population based cohort study, The BMJ, doi.org/10.1136/bmj.j1415, 12 April 2017.
  • Common drugs, uncommon risks? Higher rate of serious problems after short-term steroid use, medicalxpress, April 13, 2017.

Measuring the amount of pharmaceutical pollution in our waterways

Sewage treatment plants are not capable of filtering medicine drug residues

Scientists began sampling the Hudson river this month to measure the amount of pharmaceutical pollution in the waterway.

Residue from medicine has long polluted waterways, but has only been identified as a serious problem in recent years.

Sewage treatment plants are not capable of filtering pharmaceuticals, allowing them to pass from human and animal waste to open waters.

Pharmaceutical pollution likely caused male fish in some rivers and lakes to develop female sexual characteristics in recent years.

Improper disposal of old medicines – like flushing it down the toilet – is also a problem.

  • Read How bad is pharmaceutical pollution in the Hudson?northjersey, April 10, 2017.
  • Read Riverkeeper to present water quality data for Upper Hudson in three public events Wednesday, April 12, riverkeeper, 04.07.17.

Questioning the Safety of the Hormonal Pregnancy Test Drugs

1978 London Programme

Greg Dyke and his team, at London Weekend TV, highlight and interview parents and children on the dangers which Primodos was causing to the unborn foetus.

Part 1
Part 2
Part 3

More Information

Primodos Investigation : Jason Farrell Reveals

Jason Farrell has been investigating Primodos for six years – he talked about his experience

March 2017 : MPs have welcomed a Sky investigation, which revealed how hormone pregnancy tests may have caused malformations and even deaths.

Around 1.5 million women in Britain in the 1960s and 70s took Primodos in the early stages of pregnancy. Some say their pregnancies resulted in miscarriage or birth defects.

Sky News’ hour-long documentary Primodos: The Secret Drug Scandal is presented by senior political correspondent Jason Farrell, who has been investigating it for six years.

Sky News revealed how documents were destroyed and information withheld about a drug that may have deformed and killed babies in the womb.

More Information