Investigation raises questions over lack of “substantial evidence” for FDA approved antibiotic
Did new antibiotic meet the legal standard for approval? Are US drug regulatory rules being bypassed?
Peer-Reviewed PublicationDrugs approved in the US require “substantial evidence” that they are effective. But an investigation by The BMJ into the recent approval of the antibiotic Recarbrio from Merck suggests that these standards are being bypassed.
Peter Doshi, senior editor at The BMJ, describes how US Food and Drug Administration (FDA) scientists had serious doubts about Recarbrio - a product 40 times more expensive than an existing generic alternative - but the agency approved it anyway.
Did the FDA break its own rules in approving this antibiotic, and what does this case tell us about problems within the agency, he asks?
Recarbrio is a combination therapy made up of a new beta-lactamase inhibitor (relebactam) and a decades old Merck antibiotic (imipenem-cilastatin) to treat complicated infections. It costs between $4,000 and $15,000 for a course, compared with a couple of hundred dollars for the generic version of Merck’s old antibiotic.
In its FDA application, Merck submitted results from two clinical trials comparing Recarbrio with imipenem in adults with complicated urinary tract infections and in patients with complex intra-abdominal infections.
But FDA reviewers noted that Merck had studied the wrong patient population to evaluate the added benefits of the new drug, and said the trial for urinary tract infections showed that Recarbrio was as much as 21% worse in effectiveness than the older, less-expensive imipenem.
The FDA concluded that “these studies are not considered adequate and well-controlled.” And of a third clinical study, the FDA called it a “very small,” “difficult to interpret” “descriptive trial with no pre-specified plans for hypothesis testing.”
Yet despite all three clinical studies not providing substantial evidence of effectiveness, FDA approved Recarbrio.
“Instead of basing its decision on the clinical trials in Merck’s application, FDA’s determination of Recarbrio’s efficacy was justified on past evidence that imipenem was effective, plus - to justify the new relebactam component - in vitro (lab) studies and animal models of infection rather than evidence from human trials as required by law,” writes Doshi.
Others are concerned that Recarbrio’s approval essentially amounts to a return to a way of regulating medicines that the FDA abandoned a half century ago prior to the agency’s “substantial evidence” standard.
Doshi explains that, under specific circumstances, the Director of the Center for Drug Evaluation and Research (CDER) can waive in whole or in part the FDA’s “adequate and well-controlled studies” approval criteria. But the FDA told The BMJ ”there was no center director memo in the file” for Recarbrio.
And when The BMJ contacted Janet Woodcock, CDER Director at the time, and now the FDA’s Principal Deputy Commissioner, she said she was not aware that the clinical studies of Recarbrio did not provide substantial evidence of effectiveness.
Woodcock was also unable to confirm that approvals of new drugs require at least one clinical study of the drug itself that demonstrates substantial evidence - evidence lacking in the case of Recarbrio.
A spokesperson for CDER told The BMJ that FDA “applied regulatory flexibility” in approving Recarbrio.
It is unclear whether this regulatory flexibility enabled FDA to conclude Recarbrio had met the legal “substantial evidence” standard without “adequate and well-controlled investigations” of Recarbrio, says Doshi. FDA declined to answer the question, saying “We have no additional information to provide.”
The decline of science at the FDA has become unmanageable, argues David Ross, associate clinical professor of medicine at George Washington University, School of Medicine and Health Sciences, and former FDA medical reviewer, in a linked commentary.
He describes Recarbrio’s approval as “shocking” and says while much of the blame must go to the FDA’s reliance on industry paid user fees for around two-thirds of its annual drugs budget, “the corruption of the FDA’s scientific culture remains the primary culprit driving the deterioration of safety and effectiveness standards.”
To address this “dismal situation” he suggests tapering the FDA’s dependence on user fees and improving public access to the information received by the FDA, its reasoning, and its decisions.
“The Recarbrio approval is a sentinel event, warning of a return to an era when drug effectiveness was an afterthought,” argues Ross. “Although the FDA crowed about this approval, it would have been better advised to remember that “for a successful technology, reality must take precedence over public relations, for nature cannot be fooled,” he concludes.
JOURNAL
The BMJ
ARTICLE TITLE
Investigation: Did the FDA break its own rules in approving the antibiotic Recarbrio?
ARTICLE PUBLICATION DATE
15-May-2023
COI STATEMENT
https://www.bmj.com/about-bmj/editorial-staff/peter-doshi
Porous crystals made from plant
extracts purify water from
pharmaceutical pollutants
Researchers from Stockholm University have developed porous crystals made from pomegranate extract to capture and degrade pharmaceutical molecules found in local municipal wastewater. The research is published in the scientific journal Nature Water.
Peer-Reviewed PublicationIMAGE: PART OF AN SU-102 CRYSTAL. THE DARK AREAS ARE ONE NANOMETER WIDE PORES, THE IMAGE WAS TAKEN USING AN ELECTRON MICROSCOPE. view more
CREDIT: TOM WILLHAMMAR
Researchers from Stockholm University have developed porous crystals made from pomegranate extract to capture and degrade pharmaceutical molecules found in local municipal wastewater. The research is published in the scientific journal Nature Water.
Pharmaceutical compounds affect the human body to improve our health, but they can also have unintentional adverse effects for the wellbeing of wildlife. Hence wastewater treatment plants are facing the challenge of removing emerging organic contaminants (EOCs) such as active pharmaceutical ingredients, and therefore new materials and technologies are required.
One strategy for removing pollutants from water is by using porous materials that behave like sponges. Metal-organic frameworks, so called MOFs, are a type of nanoporous material that are made of metal ions and organic molecules. Most MOFs are made using synthetic organic molecules. But now researchers from the Department of Materials and Environmental Chemistry, Stockholm University, have managed to develop new porous MOFs using a naturally occurring molecule found in plants – ellagic acid.
“Ellagic acid is one of the main building units of naturally occurring polyphenols known as tannins, which are common in fruits, berries, nuts, and tree bark. By combining ellagic acid, which was extracted from either pomegranate peel or tree bark, with zirconium ions, we developed a new highly porous MOF which we named SU-102,” says Erik Svensson Grape, PhD student at the Department of Materials and Environmental Chemistry.
In order to test the performance of SU-102, water that had already been purified at a local wastewater treatment facility was further treated with the new MOF. The results showed that SU-102 removed many of the pharmaceutical pollutants that were not fully removed by the wastewater treatment facility. In addition to capturing the pharmaceutical pollutants, SU-102 was also used to break down pollutants using light in a process known as photodegradation.
“This has been a very exciting project as we got the opportunity to work directly with water samples from the treatment plant, thereby finding an application where our material could be put to use towards a very pressing environmental issue. We hope one day that SU-102 will be used on a bigger scale and also for other environmental applications,” says Erik Svensson Grape at Stockholm University.
JOURNAL
Nature Water
METHOD OF RESEARCH
Experimental study
SUBJECT OF RESEARCH
Not applicable
ARTICLE TITLE
Removal of pharmaceutical pollutants from effluent by a plant-based metal–organic framework
ARTICLE PUBLICATION DATE
15-May-2023
Dementia study reveals how toxic proteins spread through brain
Fresh insights into the spread of damaging proteins that build up in the brains of people with Alzheimer’s disease could hold the key to stopping the condition progressing, a study says.
Researchers have discovered that synapses, which send essential signals through the brain, are also transporting toxic proteins known as tau around the brain.
Large clumps of the protein tau – called tangles – form in brain cells and are one of the defining features of Alzheimer’s disease. As these tangles spread through the brain during the disease there is a decline in brain function.
Led by the University of Edinburgh, the study focused on synapses, connections which allow the flow of chemical and electrical messages between brain cells and are vital to healthy brain function. Alzheimer’s disease attacks synapses and their loss strongly predicts reduced memory and thinking abilities.
In the study, scientists examined more than one million synapses from 42 people using powerful microscopy techniques to visualise proteins within individual synapses.
The team discovered that small clumps of the protein tau – known as tau oligomers – are found within the synapses of people who died of Alzheimer’s disease.
Tangles of tau oligomers were seen inside both ends of the synapse – from the brain cell sending signals and the brain cell receiving signals.
In a mouse model of the disease, the oligomers jumped from one side of the synapse to the other, spreading the toxic tau through the brain.
Lowering oligomeric tau at synapses may be a promising strategy to stop disease progression in future, experts say.
Alzheimer’s disease is the most common form of dementia, with currently around 900,000 people with the condition in the UK. This figure is projected to rise to nearly 1.6 million in 2040. It can cause severe memory loss and there is currently no cure.
The study is published in the journal Neuron: https://doi.org/10.1016/j.neuron.2023.04.020. [URL will become active after embargo lifts]. The research team included scientists from the University of Edinburgh, the UK Dementia Research Institute, the Institut d'Investigacions Biomèdiques Hospital de Sant Pau and the Institute for Advanced Chemistry of Catalonia (Barcelona).
Lead researcher, Professor Tara-Spires Jones of the UK Dementia Research Institute at the University of Edinburgh, said: “We have known for over 30 years that tangles spread through the brain during Alzheimer’s disease, but how they spread has remained a mystery. Wherever tangles appear in the brain, neuron death follows, contributing to the decline in cognitive ability. Stopping the spread of toxic tau is a promising strategy to stop the disease in its tracks.”
For further information, please contact: Jess Conway, Press and PR Office, 07979 446 209 jess.conway@ed.ac.uk
JOURNAL
Neuron
METHOD OF RESEARCH
Observational study
SUBJECT OF RESEARCH
People
ARTICLE TITLE
Synaptic oligomeric tau in Alzheimer’s disease – a potential culprit in the spread of tau pathology through the brain
ARTICLE PUBLICATION DATE
15-May-2023
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