FDA’s new drug approvals : is there evidence that the public is happy to sacrifice safety for speed ?

Safety related label changes for new drugs after approval in the US through expedited regulatory pathways: retrospective cohort study

Most drugs today qualify for one of the FDA’s expedited pathways. But what is the evidence that the public is on board with the notion of sacrificing safety for speed?

What is already known on this topic
  • Recent legislation in America opens the possibility for the expansion and increased use of FDA expedited drug development and review pathways designed to respond to public health priorities
  • Evidence on whether drugs approved through expedited regulatory pathways carry higher levels of safety risks that are unknown at the time of approval is conflicting
  • Some studies suggest that the review process does not impact the quality of the safety assessment, whereas others show a difference
What this study adds
  • In this analysis concerning more than 15 years of comprehensive data, expedited pathway drugs had a 38% higher rate of safety related label changes than drugs approved through non-expedited pathways
  • As policymakers continue to expand expedited regulatory pathways, physicians and patients should be aware of the potential safety trade-offs involved in these pathways

2017 Study Abstract

To determine if drugs approved through the Food and Drug Administration’s expedited development and review pathways have different rates of safety related label changes after approval compared with drugs approved through standard non-expedited pathways.

Retrospective cohort study.

FDA public records, January 1997 to April 2016.

382 FDA approved drugs.

Main outcome measures
The number of times a particular safety section of a label (boxed warning, contraindication, warning, precaution, or adverse reaction) was changed during a drug’s time on the market. The relative rate of safety related label changes per year for expedited pathway and non-expedited pathway drugs was compared by forming matched pairs of drugs in the same therapeutic class that were approved within three years of each other.

Among the 382 eligible new drugs, 135 (35%) were associated with an expedited development or review pathway, and matches were available for 96 (71%). The matched pairs were associated with a total of 1710 safety related label changes during the study period. Expedited pathway drugs were characterized by a rate of 0.94 safety related label changes for each drug per year, compared with 0.68 safety related label changes per year for non-expedited pathway drugs (rate ratio 1.38, 95% confidence interval 1.25 to 1.52). Compared with non-expedited pathway drugs, expedited pathway drugs had a 48% higher rate of changes to boxed warnings and contraindications, the two most clinically important categories of safety warnings (1.48, 95% confidence interval 1.07 to 2.06). A qualitative review of changes to the boxed warning sections revealed that less than 5% (3/67) were changed to describe reduced risks for patients.

Expedited development and regulatory review pathways can accelerate the availability of new drugs, but drugs approved through these pathways are associated with increased safety related label changes after approval, particularly for the types of changes representing the highest risk warnings. To inform appropriate policy interventions, additional research should explore the causal factors contributing to these different rates.

More Information

  • Safety related label changes for new drugs after approval in the US through expedited regulatory pathways: retrospective cohort study, BMJ 2017;358:j3837, 07 September 2017.
  • Speed vs safety in the FDA’s new drug approvals—speed wins, again, blogs.bmj, September 12, 2017.
  • Featured image credit stickergiant.

How big data’s big bias is bringing noise and conflicts to US drug regulation

Jeanne Lenzer investigates, The BMJ, July 2017

A little known private foundation to support FDA’s “regulatory science” takes money out of the FDA’s coffers to support analyses using levels of evidence recommended by industry; many of the foundation’s directors have financial links to the drug and device makers that the FDA regulates.

  • No drug risks identified
  • Reagan-Udall Foundation
  • Directors’ ties to industry
  • Panel stacking
  • Funding the foundation
  • Funding the Medical Evidence Development and Surveillance (IMEDS)
  • Light touch FDA

Big data can be used cautiously to examine real world outcomes and to improve surveillance of drug safety. For example, it has been used to identify overuse of some interventions and can show drug and device complications in real world settings rather than idealized controlled trials.

However, big data are a noisy mess, and analyses by entities with profit motives may identify spurious associations that support fast track approvals and indication creep (broadening the indications for drugs and devices).” …

continue reading Jeanne Lenzer investigation Big data’s big bias: bringing noise and conflicts to US drug regulation on The BMJ, 18 July 2017.

About The Personal Care Products Safety Act

Bill would help protect consumers from chemicals that disrupt hormones

Endocrine Society applauds new push to regulate chemicals in personal care products

Washington, DCThe Endocrine Society praised the reintroduction of a Senate bill to ensure consumers are protected from hazards associated with exposure to chemicals in personal care products such as cosmetics and lotions.

The Personal Care Products Safety Act, co-sponsored by U.S. Sens. Dianne Feinstein and Susan Collins, would set a rigorous safety standard for personal care products and provide the public with more information about the chemicals in the products they are purchasing. This is an area of concern for the Society and its 18,000 members, including researchers studying how endocrine-disrupting chemicals (EDCs) disrupt the body’s hormones.

An EDC is a chemical or mixture of chemicals that can cause adverse health effects by interfering with hormones in the body. There are more than 85,000 manufactured chemicals, of which thousands may be EDCs. EDCs are found in everyday products and throughout the environment.
The evidence is more definitive than ever before that EDCs disrupt hormones in a manner that harms human health. EDC-related health outcomes include male reproductive disorders, premature death, obesity and diabetes, neurological impacts, breast cancer, endometriosis, female reproductive disorders, immune disorders, liver cancer, osteoporosis, Parkinson’s disease, prostate cancer and thyroid disorders.

The Personal Care Products Safety Act calls for some chemicals found in shampoo, deodorant, cosmetics and other personal care products to be reviewed for safety for the first time. The Society applauded the bill’s inclusion of propyl paraben, a potential EDC linked to reproductive disorders, as one of the first five chemicals slated for review.
By providing the necessary authority and fees for the FDA to properly regulate personal care products, the Society believes that this legislation will effectively and efficiently ensure a safer marketplace for personal care products and reduce harms from exposure to EDCs and other toxic chemicals.

Sources and Press Releases

  • Endocrine Society applauds new push to regulate chemicals in personal care products, TheEndoSociety, May 15, 2017.
  • Senators Seek Enhanced Safety Looks at Cosmetic Ingredients, promomarketing, May 15, 2017.
  • Personal Care Products Safety Act Would Improve Cosmetics Safety, ewg.
Endocrine Disruptors

Why Dissent Matters

Because Some People See Things the Rest of Us Miss

The thalidomide tragedy was averted in the United States because Dr. Kelsey, alone and in the face of fierce opposition, did her job. Her perspective was educated, fresh and unique. If there had been no thalidomide crisis, the United States, with the rest of the world following, would still at some time have brought pharmaceutical regulation into the 20th century. But thalidomide created one of those moments when something had to be done. It could not be ignored in 1961-62, and it led immediately to a better and stronger regulatory system. Maybe someone else would have stopped thalidomide in the United States had Dr. Kelsey not been assigned the NDA, but, interestingly, no one else stopped it anywhere else until it was too late. Dr. Kelsey was the only person in the entire world who said no. She said no to a bad drug application, she said no to an overbearing pharmaceutical company and she said no to vested interests who put profits first. She was one brave dissenter. In the end, the question is not what made Frances Kelsey, but why aren’t there more like her?

Because Some People See Things the Rest of Us Miss

The nature writer Rachel Carson identified an emerging environmental disaster and pulled the fire alarm. Public protests, individual dissenters, judges, and juries can change the world – and they do.

A wide-ranging and provocative work on controversial subjects, Why Dissent Matters tells a story of dissent and dissenters – people who have been attacked, bullied, ostracized, jailed, and, sometimes when it is all over, celebrated.

William Kaplan shows that dissent is noisy, messy, inconvenient, and almost always time-consuming, but that suppressing it is usually a mistake – it’s bad for the dissenter but worse for the rest of us. Drawing attention to the voices behind international protests such as Occupy Wall Street and Boycott, Divest, and Sanction, he contends that we don’t have to do what dissenters want, but we should listen to what they say. Our problems are not going away. There will always be abuses of power to confront, wrongs to right, and new opportunities for dissenting voices to say, “Stop, listen to me.” Why Dissent Matters may well lead to a different and more just future.

Read This is Dr. Frances Kelsey’s story, the globe and mail, MAY 11, 2017.

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.

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


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.


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.

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.

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.

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.

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.

The Bitterest Pill

How Drug Companies Fail to Protect Women and How Lawsuits Save Their Lives

Click to download the whole study.

Women across the country have suffered tremendously as a result of defective and dangerous drugs and medical devices. History shows that many FDA-approved drugs and devices that have caused some of the most serious injuries and death have been marketed specifically for women. This is largely due to the number of products routinely prescribed to otherwise healthy women to control some aspect of their reproductive system. In addition, some drugs have had a disproportionate impact on pregnant women and their children.

Many drugs and devices were made safer only after women and their families filed lawsuits against those responsible. Sometimes, companies that have been hit with large verdicts or settlements act immediately to change their unsafe product or practice. Lawsuits also have had a tremendously beneficial role spurring medical research and alerting the public – and ultimately pressuring regulators – to act on larger health risks and problems. As a result, the lives of countless other women have been saved.

In addition, unlike the regulatory scheme, which provides no direct benefit to victims, civil cases hold companies directly accountable to those whom they have hurt, and provide their victims with compensation to help rebuild their lives. Drug company immunity would remove the most significant and effective financial consequence to a company for choosing to keep a dangerous drug or device on the market.

DES was a synthetic estrogen approved by the FDA to prevent miscarriages. DES did not work but instead caused cancer, infertility and other serious physical problems for the women who took it, and the children they carried. For almost two decades after the drug was proven ineffective, manufacturers continued to push the drug and expose hundreds of thousands of women and their offspring to risk. Until women started bringing lawsuits, many DES exposed women did not know about the risks they faced.

  • Download the Center for Justice & Democracy whole study.
  • See more DES books on this Flickr album.
DES DiEthylStilbestrol Resources

Doctors misunderstand what FDA drug approval really means

Shouldn’t physicians and consumers hear about the negative studies?

Most doctors do not fully understand the drug approval process for the US Food and Drug Administration (FDA) or the FDA’s “breakthrough” drug classification.

” Physicians tended to overestimate the minimum evidence of efficacy required of new drugs.

Similarly, many misinterpreted the term breakthrough—believing these drugs were supported by stronger evidence than required by the statute. “

write Aaron S. Kesselheim, MD, JD, MPH, from Brigham and Women’s Hospital in Boston, Massachusetts


This survey study examines how well physicians understand the US Food and Drug Administration’s (FDA’s) statutory definition of a “breakthrough” therapy, and whether the term breakthrough affects their perceptions of a drug’s efficacy.

Physicians’ Knowledge About FDA Approval Standards and Perceptions of the “Breakthrough Therapy” Designation, JAMA. 2016; 315(14):1516-1518. , doi:10.1001/jama.2015.16984, April 12, 2016.

Before US patients can use new prescription drugs, the US Food and Drug Administration (FDA) reviews the clinical trial results to confirm that benefits outweigh harms for the indication. Approval may involve superiority to placebo, not to an active comparator or standard of care (although approval can be based on uncontrolled or historically controlled studies). Numerous pathways expedite drug development and approval for serious or life-threatening conditions. For example, since 2012, the FDA can designate a drug as a “breakthrough therapy” if preliminary clinical evidence—such as an improvement in a pharmacodynamic biomarker—suggests an advantage over existing options Through April 2015, the FDA designated 76 “breakthrough” drugs and the term is routinely used in press releases and prescribing resources.

Press releases
  • Inside the Sausage Factory of Drug Approval: Nuplazid (pimavanserin) coverage didn’t inspect closely enough, healthnewsreview, May 23, 2016.
  • Internists, Specialists Lack Knowledge About FDA Drug Approval Process, medscape, April 12, 2016.

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.
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