Drugs stalled at FDA far more likely to have unpublished trials than licensed ones: 46% vs 10%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

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

Methods
‘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.

Results
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 Based on the criteria for nonpublication in this report, 14,092 and 33,882 volunteers participated in unpublished trials of licensed and stalled neurological drugs, respectively.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.

Interpretation
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

Question
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?

Findings
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.

Meaning
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

Importance
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.

Objectives
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.

Exposures
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.

Results
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.

Can hormone replacement therapy increase the risk of hearing loss ?

The link between menopausal age, the use of oral hormonal therapy, and hearing loss

New research suggests that hormone therapy increases the risk of hearing loss among menopausal and postmenopausal women.

2017 Study Abstract

Objective

Menopause and postmenopausal hormone therapy and risk of hearing loss, menopause journal, doi: 10.1097/GME.0000000000000878, May 8, 2017.

medical news today,  articles/317387, May 10, 2017.

Image credit anthonymedicalcare.

Menopause may be a risk factor for hearing loss, and postmenopausal hormone therapy (HT) has been proposed to slow hearing decline; however, there are no large prospective studies. We prospectively examined the independent relations between menopause and postmenopausal HT and risk of self-reported hearing loss.

Methods
Prospective cohort study among 80,972 women in the Nurses’ Health Study II, baseline age 27 to 44 years, followed from 1991 to 2013. Baseline and updated information was obtained from detailed validated biennial questionnaires. Cox proportional-hazards regression models were used to examine independent associations between menopausal status and postmenopausal HT and risk of hearing loss.

Results
After 1,410,928 person-years of follow-up, 18,558 cases of hearing loss were reported. There was no significant overall association between menopausal status, natural or surgical, and risk of hearing loss. Older age at natural menopause was associated with higher risk. The multivariable-adjusted relative risk of hearing loss among women who underwent natural menopause at age 50+ years compared with those aged less than 50 years was 1.10 (95% confidence interval [CI] 1.03, 1.17). Among postmenopausal women, oral HT (estrogen therapy or estrogen plus progestogen therapy) was associated with higher risk of hearing loss, and longer duration of use was associated with higher risk (P trend < 0.001). Compared with women who never used HT, the multivariable-adjusted relative risk of hearing loss among women who used oral HT for 5 to 9.9 years was 1.15 (95% CI 1.06, 1.24) and for 10+ years was 1.21 (95% CI 1.07, 1.37).

Conclusions
Older age at menopause and longer duration of postmenopausal HT are associated with higher risk of hearing loss.

Environmental exposures start in the womb

Protecting Children from the Environment

Children, including adolescents, are exposed to a variety of hazards from the environments in which they live, learn and play.

Environmental exposures start in the womb, and can have effects throughout life.

Early exposure to environmental risks contributes to childhood cancers.

SOURCES

Diethylstilbestrol induces oxidative DNA damage

DES exposure results in apoptosis of spermatogonial stem cells in vitro

2017 Study Highlights

  • Exposure of the spermatogonial stem cells to DES produced significant increases in superoxide anion, DNA damage and apoptosis.
  • The male reproductive system can be disrupted by foetal exposure to DES.
  • The flavonoid quercetin reduced intracellular superoxide anions induced by DES.

Abstract

The spermatogonial stem cells (SSCs) are the only germline stem cells in adults that are responsible for the transmission of genetic information from mammals to the next generation. SSCs play a very important role in the maintenance of progression of spermatogenesis and help provide an understanding of the reproductive biology of future gametes and a strategy for diagnosis and treatment of infertility and male reproductive toxicity.

Androgens/oestrogens are very important for the suitable maintenance of male germ cells. There is also evidence confirming the damaging effects of oestrogen-like compounds on male reproductive health.

Diethylstilbestrol induces oxidative DNA damage, resulting in apoptosis of spermatogonial stem cells in vitro, US National Library of Medicine National Institutes of Health, Toxicology, NCBI PubMed PMID: 28315349, 2017 Mar.

Image credit Alessandro.

We investigated the effects in vitro, of diethylstilbestrol (DES) on mouse spermatogonial stem cells separated using Staput unit-gravity velocity sedimentation, evaluating any DNA damage using the Comet assay and apoptotic cells in the TUNEL assay.

Immunocytochemistry assays showed that the purity of isolated mouse spermatogonial cells was 90%, and the viability of these isolated cells was over 96%. Intracellular superoxide anion production (O2) in SSCs was detected using p-Nitro Blue Tetrazolium (NBT) assay. The viability of cells after DES treatment was examined in the CCK8 (cell counting kit-8) cytotoxicity assay.

The study results showed that DES-induced DNA damage causes an increase in intracellular superoxide anions which are reduced by the flavonoid, quercetin. Investigating the molecular mechanisms and biology of SSCs provides a better understanding of spermatogonial stem cell regulation in the testis.

DES DiEthylStilbestrol Resources

Give patients access to their medical records

If Sweden can do it, so can we all, says Fiona Godlee, theBMJ Editor in chief

Watch recorded sessions from London 2017, sign up for the Asia Forum in Kuala Lumpur in August, and Register Your Interest for the International Forum.

Last week nearly 3000 healthcare providers and users attended the International Forum for Quality and Safety in Healthcare, in London. Hosted by The BMJ and the Institute for Healthcare Improvement, it’s always an inspiring event.

Abstract

… “Patient empowerment is at the heart of a radical redesign of care and organisational restructure at Karolinska University Hospital in Sweden. Fresh from his success in turning round Radboud University Medical Centre in the Netherlands, Karolinska chief executive Melvin Samsom is determined to transform the experience of patients and has involved them at every stage.” …

…”This year Sweden will achieve universal online access of patients to their full medical records. … this has taken time, a need to overcome resistance among clinicians, and a change in the law. Other countries, including the UK, are overcoming similar challenges. Patients across the US, Canada, Australia, the Netherlands, and elsewhere in Europe are gaining access to their records, and the UK government has promised universal access by 2020.“…

Postmarketing studies after the FDA approves drugs on limited evidence

Postapproval studies of drugs initially approved by the FDA on the basis of limited evidence: systematic review

Introduction

In the US, the Food and Drug Administration determines whether a new drug is sufficiently safe and effective to be made available to doctors for use by patients. To do this, it must find a balance between requiring sufficient high quality clinical evidence from premarket evaluation and allowing promising new drugs to enter the marketplace quickly with continued evaluation after approval. The FDA maintains a “usual requirement” of “more than one” well controlled clinical trial that independently proves a drug’s efficacy. However, it also describes several situations in which fewer trials or studies with non-clinical outcomes, such as surrogate markers of disease, might suffice for premarket evaluation. Thus, FDA approval is binary, but the clinical trial evidence that forms the basis of the FDA’s decision varies widely.

Abstract

Postapproval studies of drugs initially approved by the FDA on the basis of limited evidence: systematic review, The BMJ, doi.org/10.1136/bmj.j1680, 03 May 2017.

Image credit @bmj_latest.

Objective
To characterize the prospective controlled clinical studies for all novel drugs that were initially approved by the Food and Drug Administration on the basis of limited evidence.

Design
Systematic review.

Data sources
Drugs@FDA database and PubMed.

Study inclusion
All prospective controlled clinical studies published after approval for all novel drugs initially approved by the FDA between 2005 and 2012 on the basis of a single pivotal trial, pivotal trials that used surrogate markers of disease as primary endpoints, or both.

Results
Between 2005 and 2012 the FDA approved 117 novel drugs for 123 indications on the basis of a single pivotal trial, pivotal trials that used surrogate markers of disease, or both (single surrogate trials). We identified 758 published controlled studies over a median of 5.5 years (interquartile range 3.4-8.2) after approval, most of which (554 of 758; 73.1%) were studies for indications approved on the basis of surrogate markers of disease. Most postapproval studies used active comparators—67 of 77 (87.0%) indications approved on the basis of single pivotal trials, 365 of 554 (65.9%) approvals based on surrogate marker trials, and 100 of 127 (78.7%) approvals based on single surrogate trials—and examined surrogate markers of efficacy as primary endpoints—51 of 77 (66.2%), 512 of 554 (92.4%), and 110 of 127 (86.6%), respectively. Overall, no postapproval studies were identified for 43 of the 123 (35.0%) approved indications. The median total number of postapproval studies identified was 1 (interquartile range 0-2) for indications approved on the basis of a single pivotal trial, 3 (1-8) for indications approved on the basis of pivotal trials that used surrogate markers of disease as primary endpoints, and 1 (0-2) for single surrogate trial approvals, and the median aggregate number of patients enrolled in postapproval studies was 90 (0-509), 533 (122-3633), and 38 (0-666), respectively. The proportion of approved indications with one or more randomized, controlled, double blind study using a clinical outcome for the primary endpoint that was published after approval and showed superior efficacy was 18.2% (6 of 33), 2.0% (1 of 49), and 4.9% (2 of 41), respectively.

Conclusions
The quantity and quality of postapproval clinical evidence varied substantially for novel drugs approved by the FDA on the basis of a single pivotal trial, pivotal trials that used surrogate markers of disease, or both. Fewer than 10% of approved indications had one or more published randomized controlled, double blind study showing superior efficacy based on clinical outcomes that examined the same indication for which the drug was first approved by the FDA after a median of 5.5 years after approval. These findings should inform both clinical decision making and regulatory policy regarding requirements before and after approval of novel drugs.

Maternal Phthalate Exposure Promotes Allergic Airway Inflammation over Two Generations via Epigenetic Modifications

Phthalates increase the risk of allergies among children

Phthalates, which are used as plasticizers in plastics, can considerably increase the risk of allergies among children. According to a new study, an increased risk of children developing allergic asthma exists if the mother has been particularly heavily exposed to phthalates during pregnancy and breastfeeding.

2017 Study Abstract

Background
Prenatal and early postnatal exposures to environmental factors are considered responsible for the increasing prevalence of allergic diseases. Although there is some evidence for allergy-promoting effects in children due to exposure to plasticizers like phthalates, findings of previous studies are inconsistent and lack mechanistic information.

Objective
We investigated the effect of maternal phthalate exposure on asthma development in the subsequent generations and their underlying mechanisms including epigenetic alterations.

Methods
Phthalate metabolites were measured within the prospective mother-child cohort LINA and correlated with asthma development in the children. A murine trans-generational asthma model was used to identify involved pathways.

Results
In LINA maternal urinary concentrations of mono-n-butyl phthalate, a metabolite of butyl benzyl phthalate (BBP), were associated with an increased asthma risk in the children. Using a murine trans-generational asthma model, we demonstrate a direct effect of BBP on asthma severity in the offspring with a persistently increased airway inflammation up to the F2 generation. This disease-promoting effect was mediated by a BBP-induced global DNA hypermethylation in CD4 T cells of the offspring as treatment with a DNA demethylating agent alleviated exacerbation of allergic airway inflammation. 13 transcriptionally down-regulated genes linked to promoter or enhancer hypermethylation were identified. Among these, the GATA-3 repressor Zfpm1 emerged as a potential mediator of the enhanced susceptibility for Th2-driven allergic asthma.

Conclusion
These data provide strong evidence that maternal BBP exposure increases the risk for allergic airway inflammation in the offspring by modulating the expression of genes involved in Th2 differentiation via epigenetic alterations.

Sources and Press Releases
  • Maternal Phthalate Exposure Promotes Allergic Airway Inflammation over Two Generations Via Epigenetic Modifications, jacionline, DOI: 10.1016/j.jaci.2017.03.017, 1 March 2017.
  • Phthalates increase the risk of allergies among children, medicalxpress, May 3, 2017.
  • Image credit: UFZ/André KünzelmannIn the course of the LINA mother-child cohort study, UFZ scientists investigated the lifestyle and environmental factors of pregnant women and their influence on the allergy risk of infants.

The persistence of DDT and POPs chemicals contamination and the extinction risk for our wildlife

Extinction Risk for Many Species of Plants and Animals are Higher Than Suspected

A new study indicates that the number of plant and animal species at risk of extinction may be considerably higher than previously thought. A team of researchers, however, believe they’ve come up with a formula that will help paint a more accurate picture.

2017 Study Highlights

  • Range maps used by IUCN for threat assessment are inaccurate and mostly overestimated.
  • Citizen science, georeferenced ecological data, and distribution modeling allow accurate range estimates.
  • We found the ranges of 17 of 18 Western Ghats endemic bird species overestimated.
  • We also found 10 of those species requiring an uplisting of their IUCN threat status.
  • Methods used here to refine range estimates have conservation implications for taxa worldwide.

Abstract

The validity of the threat status assigned to a species by the International Union for Conservation of Nature’s (IUCN) Red List relies heavily on the accuracy of the geographic range size estimate for that species. Range maps used to assess threat status often contain large areas of unsuitable habitat, thereby overestimating range and underestimating threat. In this study, we assessed 18 endemic birds of the Western Ghats to test the accuracy of the geographic range sizes used by the IUCN for their threat assessment.

Using independently reviewed data from the world’s largest citizen science database (eBird) within a species distribution modeling framework, our results show that:

  • geographic ranges have been vastly overestimated by IUCN for 17 of the 18 endemic bird species;
  • range maps used by IUCN contain large areas of unsuitable habitat,
  • and ranges estimated in this study suggest provisional uplisting of IUCN threat status for at least 10 of the 18 species based on area metrics used by the IUCN for threat assessment.

Since global range size is an important parameter for assigning IUCN threat status, citizen science datasets, high resolution and freely available geo-referenced ecological data, and the latest species distribution modeling techniques should be used to estimate and track changes in range extent whenever possible. The methods used here to significantly revise range estimates have important conservation management implications not only for endemic birds in the Western Ghats, but for vertebrate and invertebrate taxa worldwide.

Sources and Press Releases
  • IUCN greatly underestimates threat levels of endemic birds in the Western Ghats, science direct, doi.org/10.1016/j.biocon.2017.03.019, 26 April 2017.
  • Extinction risk for many species vastly underestimated, study suggests, phys.org, April 25, 2017.
  • Extinction Risk For Many Species Of Plants & Animals Are Higher Than Suspected, science times, Apr 30, 2017.
  • Image Credit: V. Ramesh et al. / Biological Conservation – The new models identified 10 species in need of potential uplisting on IUCN’s Red List. The white portion of pie chart shows percent suitable habitat within IUCN range, the blue portion shows percent of the range where unsuitable or no habitats are predicted.

Clarity on future of chemicals regulation is needed

MPs call for post-Brexit UK to remain as close as possible to EU’s main chemicals law REACH

The Environmental Audit Committee urges the Government to provide clarity on the future of chemicals regulation after the EU Referendum.

Government must provide certainty

The Environmental Audit Committee has said the Government must urgently provide certainty to the UK chemicals industry over the future of chemicals regulation. The UK chemicals industry is the second largest exporter to the EU after cars, selling almost £15bn of chemical products into the European single market a year.

UK companies will have spent an estimated £250 million in order to comply with an EU registration deadline in May 2018, yet have received no guarantees over whether these registrations will remain valid after the UK leaves the EU. This uncertainty means that one in five UK chemicals companies represented by the Chemical Business Association are already investigating registering elsewhere in the EU, in a move that could cost jobs and investment.

Chair’s comment

“It is disappointing the Government have not provided the certainty that UK businesses urgently need on their plans for the future chemical regulation in the UK. The timing of Brexit means that companies face significant costs to comply with EU regulations before we leave, with no guarantee that that investment will be useful to them in the future. The lack of Government clarity is causing uncertainty and driving billions of pounds worth of businesses to consider leaving our country for the EU. The Government needs to provide certainty to ensure that it encourages continued chemical business investment in the UK.

“This lack of clarity extends to plans for a future chemicals framework for the UK: the Government has admitted that it will be difficult to transpose regulations such as REACH into UK law, yet it has not yet offered a vision for the replacement. The Government needs to ensure it understands the complexity and importance of current regulations in enabling the UK chemicals industry to provide not only value to the economy but their expertise and high standards in protecting public health and the environment.”

said Mary Creagh MP, Chair of the Environmental Audit Committee.

Value to the economy

The Environmental Audit Committee’s report highlights the crucial importance of regulation in enabling the UK chemicals industry to provide value to the economy whilst also protecting public health and the environment. The Committee urges any future Government to ensure this industry is not forgotten during EU negotiations and the development of any future domestic legislative framework for chemicals.

The committee’s key findings are:
  • The chemicals regulation framework established by the EU through REACH is difficult to transpose directly into UK law. Writing EU regulations into UK law could not be done simply by having a line in the “Great Repeal Bill” deeming REACH to apply in the UK. REACH was written from the perspective of participants being within the EU, with much of it also relating to Member State co-operation and mutual obligations, oversight and controls, and freedom of movement of products.
  • Companies face significant uncertainty over the validity of current REACH registrations after the UK leaves the EU: the Government must clarify their position on the future regulatory framework as a matter of urgency. Companies face significant costs relating to the upcoming REACH registration deadline in May 2018, yet it is unclear whether these registrations will remain valid once the UK leaves the EU in 2019. This uncertainty may already be having an impact on long-term investment decisions by companies.
  • In deciding the future of the UK’s relationship with the EU’s single market for chemicals, the Government should take a pragmatic approach. The most important element of REACH, which the Government should seek to remain involved in as a minimum, is the registration process for chemicals. Most of our respondents, from both environmental and industry perspectives, wanted to stay as closely aligned to REACH as possible. Involvement in registration would allow UK companies to share testing data with EU companies, sharing costs and allowing them to enter the market without double registration, even if the UK adopts higher standards of chemicals protection.
  • Establishing a stand-alone UK system of chemicals regulation is likely to be expensive for both the taxpayer and for industry. The Government did not provide us with detail of their scenario planning, although they did admit that the cost of taking on the roles currently provided by the European Chemicals Agency could be in the “tens of millions” of pounds.
  • The experiences of the US as it introduces an improved system of chemicals regulation could be useful for the Government when planning the UK’s approach. The US is in the process of updating its federal chemicals regulations following the introduction of new legislation in June 2016. Federal agencies are currently developing their new approach to the assessment and regulation of chemicals, and the experiences of the US in developing its own system may prove useful to the UK.
Further information