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This week, I’m rerunning some popular posts while we put the finishing touches on DCI’s new 2024-25 Economic Report on Pharmaceutical Wholesalers and Specialty Distributors.

Last week, the Federal Trade Commission (FTC) released the redacted version of administrative complaint against the three largest pharmacy benefit managers (PBMs). The FTC rightly calls out how the gross-to-net bubble can raise patients’ out-of-pocket costs, while also acknowledging how rebates can reduce a plan's (but not the patient’s) costs. Apparently, the FTC believes that PBMs’ customers are pretty dumb, because PBMs are able to prevent plans from “appreciating” such healthcare financing dynamics.

Section V.E. of the complaint (starting on page 23) focuses on the PBMs’ alleged unlawful conduct related to preferring high-list/high-rebate insulin products over versions with lower list prices. I thought it would therefore be fun to take the Wayback Machine to November 2021, when I wrote about this specific topic.

Below, you can review my commentary about the warped incentives behind Viatris’ dual-pricing strategy for its interchangeable biosimilar of Lantus. Much of the FTC’s description of the drug channel aligns with my commentary. But before you fist pump too hard for Ms. Khan’s FTC, you should pause to reflect on the agency’s legal theories in light of plans’ revealed preferences.

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The Food & Drug Administration (FDA) recently approved the first interchangeable biosimilar insulin product: the insulin glargine-yfgn injection from Viatris. Read the FDA’s press release.

Alas, I’m sad to report that the warped incentives baked into the U.S. drug channel will limit the impact of this impressive breakthrough.

Viatris is being forced to launch both a high-priced and a low-priced version of the biosimilar. However, only the high-list/high-rebate, branded version will be available on Express Scripts’ largest commercial formulary. Express Scripts will block both the branded reference product and the lower-priced, unbranded—but also interchangeable—version. Meanwhile, Prime Therapeutics will place both versions on its formularies, leaving the choice up to its plan sponsor clients.

Consequently, many commercial payers will adopt the more expensive product instead of the identical—but cheaper—version. As usual, patients will be the ultimate victims of our current drug pricing system.

Below, I explain the weird economics behind this decision, highlight the negative impact on patients, and speculate on what this all could mean for biosimilars’ future. Until plan sponsors break their addiction to rebates, today’s U.S. drug channel problems will remain.
Read more »

<p>On 3^&nbsp;June 2024,&nbsp;Resolution&nbsp;RDC No. 876 was published in Brazil in the Official Journal of the Union (DOU)[1],&nbsp;modifying the current regulations regarding the post-registration of biological products (RDC 413/2020).</p>

Results reporting requirements are pretty clear. Maybe critics should re-check their methods?

Ben Goldacre has rather famously described the clinical trial reporting requirements in the Food and Drug Administration Amendments Act of 2007 as a “fake fix” that was being thoroughly “ignored” by the pharmaceutical industry.

Pharma: breaking the law in broad daylight?

He makes this sweeping, unconditional proclamation about the industry and its regulators on the basis of  a single study in the BMJ, blithely ignoring the fact that a) the authors of the study admitted that they could not adequately determine the number of studies that were meeting FDAAA requirements and b) a subsequent FDA review that identified only 15 trials potentially out of compliance, out of a pool of thousands.


Despite the fact that the FDA, which has access to more data, says that only a tiny fraction of studies are potentially noncompliant, Goldacre's frequently repeated claims that the law is being ignored seems to have caught on in the general run of journalistic and academic discussions about FDAAA.

And now there appears to be additional support for the idea that a large percentage of studies are noncompliant with FDAAA results reporting requirements, in the form of a new study in the Journal of Clinical Oncology: "Public Availability of Results of Trials Assessing Cancer Drugs in the United States" by Thi-Anh-Hoa Nguyen, et al.. In it, the authors report even lower levels of FDAAA compliance – a mere 20% of randomized clinical trials met requirements of posting results on clinicaltrials.gov within one year.

Unsurprisingly, the JCO results were immediately picked up and circulated uncritically by the usual suspects.

I have to admit not knowing much about pure academic and cooperative group trial operations, but I do know a lot about industry-run trials – simply put, I find the data as presented in the JCO study impossible to believe. Everyone I work with in pharma trials is painfully aware of the regulatory environment they work in. FDAAA compliance is a given, a no-brainer: large internal legal and compliance teams are everywhere, ensuring that the letter of the law is followed in clinical trial conduct. If anything, pharma sponsors are twitchily over-compliant with these kinds of regulations (for example, most still adhere to 100% verification of source documentation – sending monitors to physically examine every single record of every single enrolled patient - even after the FDA explicitly told them they didn't have to).

I realize that’s anecdotal evidence, but when such behavior is so pervasive, it’s difficult to buy into data that says it’s not happening at all. The idea that all pharmaceutical companies are ignoring a highly visible law that’s been on the books for 6 years is extraordinary. Are they really so brazenly breaking the rules? And is FDA abetting them by disseminating incorrect information?

Those are extraordinary claims, and would seem to require extraordinary evidence. The BMJ study had clear limitations that make its implications entirely unclear. Is the JCO article any better?

Some Issues

In fact, there appear to be at least two major issues that may have seriously compromised the JCO findings:

1. Studies that were certified as being eligible for delayed reporting requirements, but do not have their certification date listed.

The study authors make what I believe to be a completely unwarranted assumption:

In trials for approval of new drugs or approval for a new indication, a certification [permitting delayed results reporting] should be posted within 1 year and should be publicly available.

It’s unclear to me why the authors think the certifications “should be” publicly available. In re-reading FDAAA section 801, I don’t see any reference to that being a requirement. I suppose I could have missed it, but the authors provide a citation to a page that clearly does not list any such requirement.

But their methodology assumes that all trials that have a certification will have it posted:

If no results were posted at ClinicalTrials.gov, we determined whether the responsible party submitted a certification. In this case, we recorded the date of submission of the certification to ClinicalTrials.gov.

If a sponsor gets approval from FDA to delay reporting (as is routine for all drugs that are either not approved for any indication, or being studied for a new indication – i.e., the overwhelming majority of pharma drug trials), but doesn't post that approval on the registry, the JCO authors deem that trial “noncompliant”. This is not warranted: the company may have simply chosen not to post the certification despite being entirely FDAAA compliant.

2. Studies that were previously certified for delayed reporting and subsequently reported results

It is hard to tell how the authors treated this rather-substantial category of trials. If a trial was certified for delayed results reporting, but then subsequently published results, the certification date becomes difficult to find. Indeed, it appears in the case where there were results, the authors simply looked at the time from study completion to results posting. In effect, this would re-classify almost every single one of these trials from compliant to non-compliant. Consider this example trial:

• Phase 3 trial completes January 2010
• Certification of delayed results obtained December 2010 (compliant)
• FDA approval June 2013
• Results posted July 2013 (compliant)

In looking at the JCO paper's methods section, it really appears that this trial would be classified as reporting results 3.5 years after completion, and therefore be considered noncompliant with FDAAA. In fact, this trial is entirely kosher, and would be extremely typical for many phase 2 and 3 trials in industry.

Time for Some Data Transparency

The above two concerns may, in fact, be non-issues. They certainly appear to be implied in the JCO paper, but the wording isn't terribly detailed and could easily be giving me the wrong impression.

However, if either or both of these issues are real, they may affect the vast majority of "noncompliant" trials in this study. Given the fact that most clinical trials are either looking at new drugs, or looking at new indications for new drugs, these two issues may entirely explain the gap between the JCO study and the unequivocal FDA statements that contradict it.

I hope that, given the importance of transparency in research, the authors will be willing to post their data set publicly so that others can review their assumptions and independently verify their conclusions. It would be more than a bit ironic otherwise.
Thi-Anh-Hoa Nguyen, Agnes Dechartres, Soraya Belgherbi, and Philippe Ravaud (2013). Public Availability of Results of Trials Assessing Cancer Drugs in the United States JOURNAL OF CLINICAL ONCOLOGY DOI: 10.1200/JCO.2012.46.9577

Elemind, a 5-year-old startup based in Cambridge, Mass., today unveiled a US $349 wearable for neuromodulation, the company’s first product. According to cofounder and CEO Meredith Perry, the technology tracks the oscillation of brain waves using electroencephalography (EEG) sensors that detect the electrical activity of the brain and then influence those oscillations using bursts of sound delivered via bone conduction.

Elemind’s first application for this wearable aims to suppress alpha waves to help induce sleep. There are other wearables on the market that monitor brain waves and, through biofeedback, encourage users to actively modify their alpha patterns. Elemind’s headband appears to be the first device to use sound to directly influence the brain waves of a passive user.

In a clinical trial, says Perry [no relation to author], 76 percent of subjects fell asleep more quickly. Those who did see a difference averaged 48 percent less time to progress from awake to asleep. The results were similar to those of comparable trials of pharmaceutical sleep aids, Perry indicated.

“For me,” Perry said, “it cuts through my rumination, quiets my thinking. It’s like noise cancellation for the brain.”

I briefly tested Elemind’s headband in May. I found it comfortable, with a thick cushioned band that sits across the forehead connected to a stretchy elastic loop to keep it in place. In the band are multiple EEG electrodes, a processor, a three-axis accelerometer, a rechargeable lithium-polymer battery, and custom electronics that gather the brain’s electrical signals, estimate their phase, and generate pink noise through a bone-conduction speaker. The whole thing weighs about 60 grams—about as much as a small kiwi fruit.

My test conditions were far from optimal for sleep: early afternoon, a fairly bright conference room, a beanbag chair as bed, and a vent blowing. And my test lasted just 4 minutes. I can say that I didn’t find the little bursts of pink noise (white noise without the higher frequencies) unpleasant. And since I often wear an eye mask, feeling fabric on my face wasn’t disturbing. It wasn’t the time or place to try for sound sleep, but I—and the others in the room—noted that after 2 minutes I was yawning like crazy.

How Elemind tweaks brain waves

What was going on in my brain? Briefly, different brain states are associated with different frequencies of waves. Someone who is relaxed with eyes closed but not asleep produces alpha waves at around 10 hertz. As they drift off to sleep, the alpha waves are supplanted by theta waves, at around 5 Hz. Eventually, the delta waves of deep sleep show up at around 1 Hz.

Ryan Neely, Elemind’s vice president of science and research, explains: “As soon as you put the headband on,” he says, “the EEG system starts running. It uses straightforward signal processing with bandpass filtering to isolate the activity in the 8- to 12-Hz frequency range—the alpha band.”

“Then,” Neely continues, “our algorithm looks at the filtered signal to identify the phase of each oscillation and determines when to generate bursts of pink noise.”

To help a user fall asleep more quickly [top], bursts of pink noise are timed to generate a brain response that is out of phase with alpha waves and so suppresses them. To enhance deep sleep [bottom], the pink noise is timed to generate a brain response that is in phase with delta waves.Source: Elemind

These auditory stimuli, he explains, create ripples in the waves coming from the brain. Elemind’s system tries to align these ripples with a particular phase in the wave. Because there is a gap between the stimulus and the evoked response, Elemind tested its system on 21 people and calculated the average delay, taking that into account when determining when to trigger a sound.

To induce sleep, Elemind’s headband targets the trough in the alpha wave, the point at which the brain is most excitable, Neely says.

“You can think of the alpha rhythm as a gate for communication between different areas of the brain,” he says. “By interfering with that communication, that coordination between different brain areas, you can disrupt patterns, like the ruminations that keep you awake.”

With these alpha waves suppressed, Neely says, the slower oscillations, like the theta waves of light sleep, take over.

Elemind doesn’t plan to stop there. The company plans to add an algorithm that addresses delta waves, the low-frequency 0.5- to 2-Hz waves characteristic of deep sleep. Here, Elemind’s technology will attempt to amplify this pattern with the intent of improving sleep quality.

Is this safe? Yes, Neely says, because auditory stimulation is self-limiting. “Your brain waves have a natural space they can occupy,” he explains, “and this stimulation just moved it within that natural space, unlike deep-brain stimulation, which can move the brain activity outside natural parameters.”

Going beyond sleep to sedation, memory, and mental health

Applications may eventually go beyond inducing and enhancing sleep. Researchers at the University of Washington and McGill University have completed a clinical study to determine if Elemind’s technology can be used to increase the pain threshold of subjects undergoing sedation. The results are being prepared for peer review.

Elemind is also working with a team involving researchers at McGill and the Leuven Brain Institute to determine if the technology can enhance memory consolidation in deep sleep and perhaps have some usefulness for people with mild cognitive impairment and other memory disorders.

Neely would love to see more applications investigated in the future.

“Inverse alpha stimulation [enhancing instead of suppressing the signal] could increase arousal,” he says. “That’s something I’d love to look into. And looking into mental-health treatment would be interesting, because phase coupling between the different brain regions appears to be an important factor in depression and anxiety disorders.”

Perry, who previously founded the wireless power startup UBeam, cofounded Elemind with four university professors with expertise in neuroscience, optogenetics, biomedical engineering, and artificial intelligence. The company has $12 million in funding to date and currently has 13 employees.

Preorders at $349 start today for beta units, and Elemind expects to start general sales later this year. The company will offer customers an optional membership at $7 to $13 monthly that will allow cloud storage of sleep data and access to new apps as they are released.

A Barcelona-based startup called Inbrain Neuroelectronics has produced a novel brain implant made of graphene and is gearing up for its first in-human test this summer.

The technology is a type of brain-computer interface. BCIs have garnered interest because they record signals from the brain and transmit them to a computer for analysis. They have been used for medical diagnostics, as communication devices for people who can’t speak, and to control external equipment, including robotic limbs. But Inbrain intends to transform its BCI technology into a therapeutic tool for patients with neurological issues such as Parkinson’s disease.

Because Inbrain’s chip is made of graphene, the neural interface has some interesting properties, including the ability to be used to both record from and stimulate the brain. That bidirectionality comes from addressing a key problem with the metallic chips typically used in BCI technology: Faradaic reactions. Faradaic reactions are a particular type of electrochemical processes that occurs between a metal electrode and an electrolyte solution. As it so happens, neural tissue is largely composed of aqueous electrolytes. Over time, these Faradaic reactions reduce the effectiveness of the metallic chips.

That’s why Inbrain replaced the metals typically used in such chips with graphene, a material with great electrical conductivity. “Metals have Faraday reactions that actually make all the electrons interact with each other, degrading their effectiveness...for transmitting signals back to the brain,” said Carolina Aguilar, CEO and cofounder of Inbrain.

Because graphene is essentially carbon and not a metal, Aguilar says the chip can inject 200 times as much charge without creating a Faradic reaction. As a result, the material is stable over the millions of pulses of stimulation required of a therapeutic tool. While Inbrain is not yet testing the chip for brain stimulation, the company expects to reach that goal in due time.

The graphene-based chip is produced on a wafer using traditional semiconductor technology, according to Aguilar. At clean-room facilities, Inbrain fabricates a 10-micrometer-thick chip. The chip consists of what Aguilar terms “graphene dots” (not to be confused with graphene quantum dots) that range in size from 25 to 300 micrometers. “This micrometer scale allows us to get that unique resolution on the decoding of the signals from the brain, and also provides us with the micrometric stimulation or modulation of the brain,” added Aguilar.

Testing the Graphene-Based BCI

The first test of the platform in a human patient will soon be performed at the University of Manchester, in England, where it will serve as an interface during the resection of a brain tumor. When resecting a tumor, surgeons must ensure that they don’t damage areas like the brain’s language centers so the patient isn’t impaired after the surgery. “The chip is positioned during the tumor resection so that it can read, at a very high resolution, the signals that tell the surgeon where there is a tumor and where there is not a tumor,” says Aguilar. That should enable the surgeons to extract the tumor with micrometric precision while preserving functional areas like speech and cognition.

Aguilar added, “We have taken this approach for our first human test because it is a very reliable and quick path to prove the safety of graphene, but also demonstrate the potential of what it can do in comparison to metal technology that is used today.”

Aguilar stresses that the Inbrain team has already tested the graphene-based chip’s biocompatibility. “We have been working for the last three years in biocompatibility through various safety studies in large animals,” said Aguilar. “So now we can have these green lights to prove an additional level of safety with humans.”

While this test of the chip at Manchester is aimed at aiding in brain tumor surgery, the same technology could eventually be used to help Parkinson’s patients. Toward this aim, Inbrain’s system was granted Breakthrough Device Designation last September from the U.S. Food & Drug Administration as an adjunctive therapy for treating Parkinson’s disease. “For Parkinson’s treatment, we have been working on different preclinical studies that have shown reasonable proof of superiority versus current commercial technology in the [reduction] of Parkinson’s disease symptoms,” said Aguilar.

For treating Parkinson’s, Inbrain’s chip connects with the nigrostriatal pathway in the brain that is critical for movements. The chip will first decode the intention message from the brain that triggers a step or the lifting of the arm—something that a typical BCI can do. But Inbrain’s chip, with its micrometric precision, can also decode pathological biomarkers related to Parkinson’s symptoms, such as tremors, rigidity, and freezing of the gait.

By determining these biomarkers with great precision, Inbrain’s technology can determine how well a patient’s current drug regimen is working. In this first iteration of the Inbrain chip, it doesn’t treat the symptoms of Parkinson’s directly, but instead makes it possible to better target and reduce the amount of drugs that are used in treatment.

“Parkinson’s patients take huge amounts of drugs that have to be changed over time just to keep up with the growing resistance patients develop to the power of the drug,” said Aguilar. “We can reduce it at least 50 percent and hopefully in the future more as our devices become precise.”

As a group of friends circled a hearse, chants were heard. Then, they stopped and bowed to the portrait displayed at the front of the vehicle. This was not a typical Buddhist funeral, but rather the unconventional birthday celebration of a funeral director, reported Shin Min Daily News. According to the Chinese evening daily, a video circulating online showed the friends chanting a birthday song. The hearse's interior had been decorated with balloons and a birthday banner, with the man even laying inside for photos. The clip garnered criticism from netizens, with some deeming it overboard and disrespectful to the funeral industry. In an interview with Shin Min, director of Xin An Funeral Services Chen Weisong (transliteration) explained that he had celebrated his birthday at the company's premises with his friends and family last week. Halfway through the performances by singers, his employees and business partners had surprised him with the birthday-themed hearse bearing his portrait. Chen told 8world he was not angry and did not think it was taboo. "I was too embarrassed to turn down their gesture," he said. 

Jul 28, 2024

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