Thank you Ryan, Some of these recent articles and comments on Paxlovid have been worrisome. The closer look you guide us through helped greatly to clarify the evidence. If I get covid I would want Paxlovid; probably 10 days.
Marty (aka old, therefor high risk, retired Pulmonary/Critical Care doc).
The recent naysaying on Paxlovid makes me think of that Cochrane study that threw everyone into another round of turmoil on masking. I couldn’t follow all the detail of what you wrote here, but it’s invaluable that you have laid out all the important studies in one post. Even in broad strokes, it seems clear to me Paxlovid is valuable. (I only wish I could swallow those pills, but I am glad for those who can.) As you also so generously pointed out in a comment to me asking about this previously, the focus on alleviation of symptoms is misplaced. In addition, this certainly leapt out at me: “Participants were considered “treated with Paxlovid” even if they took just 1 pill. 1 pill total.” Shouldn’t that, all on its own, render the study invalid as to what it purports to show? Anyway, good on you for putting your valuable time, effort, and intelligence to correcting the record.
This was a very timely article. I recently had a conversation with a friend of mine. We were just catching up about our lives and I mentioned I had a funeral to attend this week. The person was 37 and very fit. He was my personal trainer and helped guide me in my weight loss journey. My friend asked if he had been vaccinated for Covid as the vaccinated die from Complications.
I tried to explain that she was jumping to conclusions based on lack of knowledge. However, since she worked in a medical office she saw things that she said were all caused by the vaccines. Thanks to articles like this one, I didn't convince her completely, but she admitted she didn't have enough facts to conclude that the vaccine gave my trainer a heart attack or was the cause of much of what she saw.
Thanks for covering this study, it's significant given we have few medications in the fight against Covid. What struck me: Smallish study, ages varied from 18-87, looks like it combined the unvaccinated and vaccinated instead of separating them out. Delta was the dominant variant and we're way passed it now. Some subjects didn't finish the full course of Paxlovid - so why even include them? And while it found that Paxlovid didn't significantly alleviate symptoms of Covid compared with the placebo, it did show a higher rate of severe events in the placebo group compared to the Paxlovid group. I still take lots of precautions to avoid Covid. But, should I get it, my bottom line is about staying out of the hospital, ICU, morgue or developing Long Covid. For me, the findings from this study aren't significant enough to prevent me from asking for a prescription.
Which leads me to this question: Can a provider deny a patient a prescription for Paxlovid - NEJM is held in high regard by many in the medical profession. Also, if I was still able to get a prescription, is it reasonable or even possible to get a 10 versus 5 days course of medication?
Among all the wicked smart ideas and syntheses in this post, I most appreciate the “dem apples“ reference to Matt Damon’s character in Goodwill Hunting?
I think he would be proud of your efforts here in the face of the New England Journal Ivory Tower 👌💪
Thanks but you need to return that soapbox to me now (lol). There were some serious rebuttals and glad you went to school on me. 😏 Sadly, with way too many PC reluctant to take the time for drug-drug interactions, renal function adjusted or just using the 'rebound' excuse, we really didn't need this. One peeve is as I've mentioned is using the same endpoint of symptoms alleviation as influenza and how often has it was said this isn't the flu. You saw the study on antibiotics didn't reduce LRTI cough and even increase it. Interesting to note that the end point was reached as 12 and 13 days that coincide with the inflammatory phase (mythically called 'rebound') of a biphasic disease. Oh dear, now I got to get off the soapbox. Good news is that is no change in the guideline per IDSA and HHS (NIH no longer updates theirs). https://aspr.hhs.gov/COVID-19/Treatments/Pages/Possible-Treatment-Options-for-COVID19.aspx
Thank you for this deep dive. The NEJM study was available from clinical trials.gov since last September, so why publish it now? We have literally only one other oral medicine, don’t trash the more effective one. And symptom reduction is not the important end point.
Just like your invaluable “Covidlandia” construct, this is another wonderful contribution. I am so bummed that testtotreat ended 4/16, it was an option for those of us who would want treatment and worry about providers and pharmacists who may create barriers.
I forwarded this to my primary care physician's group practice, with the following preamble:
“I don't expect anyone to actually read the lengthy forwarded information below, but I want it on the record, in my file or chart or whatever it's called—and the next time I come down with COVID-19, I hope y'all will help me get Paxlovid for it without delay (or any static), unlike last time. I am at high risk for COVID-19 complications—I'm 66, and I'm an obese hypertensive diabetic, for crying out loud! I've had it twice already, and the risk only increases. I don't want to die of COVID-19. Thank you.”
Is there more room on the soapbox :) because as a patient this matters to me. Compared to the NEJM study, this cohort study from March 2023 published in JAMA Internal Medicine (Dr. Ziyad Al-Aly, who has studied Post Covid Complications (PCC) as much as anyone, being one of the authors), looked at almost 282K people with Covid that had at least 1 risk factor for progression to severe illness. It found Paxlovid used in the acute phase was associated with reduced risk of PCC including reduced risk in several organ systems, post–acute death and post–acute hospitalization. It included unvaccinated, vaccinated and boosted, as well as people with primary infection and reinfection, compared with 246K who had no treatment.
JAMA Intern Med. 2023;183(6):554-564. doi:10.1001/jamainternmed.2023.0743 Published online March 23, 2023. Corrected on January 16, 2024
Thank you. I knew we could count on you to provide context and thoughtful, clear analysis. This is very helpful.
To gauge your pt's risk for severe outcomes or for LC (or for benefitting from a mid-year boost), what factors do you consider beyond age, organ system issues, and immunocompromise? There's a long list of what I call second tier factors, and I can't discern how strong the connection/risk might be. I'd prefer one of your office post-its over the CDC's spotty guidance. Thanks so much for your work.
I had to share this comment from another site I cross posted to... I never heard of this, but it may prove prophetic, and either way it is a fascinating window into the machinations behind the science in some cases:
Commenter:
"4 years in the industry and 20 at FDA.
This looks like possible Life Cycle Management to me. [It may have a new name now. Renaming existing ideas is faster and cheaper than coming up with new ideas.]
To be absolutely clear, LCM is practiced industrywide. No company has a monopoly on it, all companies do it to a greater or lesser extent, because our regulations allow it. It has a limited number of fairly predictable moves, once you’ve seen how it works.
Note the affiliation of all the authors, and the study site.
Note the relatively small n and the ITT — sorry, intent to treat analysis — that guarantees a high dropout rate will strongly bias results against the drug. When people drop out after one dose, the last observation carried forward is not going to be friendly to the drug, unless they all dropped out because they were instantaneously healed. By the way, that kind of thing — early dropouts due to high efficacy — has actually been seen, and studies are then terminated early for ethical reasons [not leaving people on placebo when there is no further need for a placebo group].
Note the study population.
Note the publication in a top tier journal and the interesting tendency of the audience to “turn on” the drug uncritically. Are there “thought leaders” among those critics? I didn’t work in that area, I wouldn’t know the names. But I wouldn’t be surprised if there are.
Based on prior experience with how LCM works, I will be quite surprised if we don’t see press releases about a theoretical successor drug soon. They may even already be out there.
I’d guess there might be requests for fast track development and then for priority review. And if I were a betting woman, I’d bet on requests for acceptance of one large Phase 2 study performed at two sites in lieu of a Phase III study.
Non-US sites may be used. It’s obnoxious to send inspectors out to them. And studies conducted entirely outside the US are not generally registered with clinicaltrials.gov. clinicaltrials.gov/...
If LCM works as intended the new product will also cost much more than the original treatment, which will be withdrawn from the market shortly after the successor is approved, for “business reasons”.
Again, these are standard LCM type moves industrywide nowadays. Keep that in mind.
Also, one can reconstruct the trajectory I’ve predicted by looking at a company’s press releases, blurbs about new drugs in development that appear in the trade press, and, once approved, the clinical trials section of the package insert. Companies brag about fast track development and priority review, so the press releases will usually confirm if these happen. Publications related to the pivotal trials will indicate study sites. Thus, none of these predictions impinges on anything that could be considered trade secret.
The next link talks about what an interested reader can glean from the clinical trials section of an approved drug’s package insert… www.pharmacytimes.com/…
And once more I will reiterate: this is standard operating procedure. I personally am no fan, since the time pressures involved do mean that problems are not always caught during the trial stage. Sometimes a drug will be taken off the market post approval because the smaller, faster studies did not include enough people to detect a particular side effect.
But this is how drug development unfolds in the US nowadays."
Thank you very much, Ryan. At 86, there are good days, and not-so-good days. It is what it is. Covid has changed the trajectory of ALL our lives. I appreciate greatly your time and effort in gathering and giving this information. I only had Covid one time, not very seriously, but the potential for serious impact cannot be denied. I am extremely grateful for your sound and sane reporting.
Thank you for doing this. I just spoke with a colleague who's 79-year-old husband was talked out of Paxlovid by his primary doc because of rebound and that it can cause long covid (!?). Now it sounds like he's developing neurological consequences to having had covid.... I will be sharing your article with many people.
Thank you Ryan, Some of these recent articles and comments on Paxlovid have been worrisome. The closer look you guide us through helped greatly to clarify the evidence. If I get covid I would want Paxlovid; probably 10 days.
Marty (aka old, therefor high risk, retired Pulmonary/Critical Care doc).
The recent naysaying on Paxlovid makes me think of that Cochrane study that threw everyone into another round of turmoil on masking. I couldn’t follow all the detail of what you wrote here, but it’s invaluable that you have laid out all the important studies in one post. Even in broad strokes, it seems clear to me Paxlovid is valuable. (I only wish I could swallow those pills, but I am glad for those who can.) As you also so generously pointed out in a comment to me asking about this previously, the focus on alleviation of symptoms is misplaced. In addition, this certainly leapt out at me: “Participants were considered “treated with Paxlovid” even if they took just 1 pill. 1 pill total.” Shouldn’t that, all on its own, render the study invalid as to what it purports to show? Anyway, good on you for putting your valuable time, effort, and intelligence to correcting the record.
This was a very timely article. I recently had a conversation with a friend of mine. We were just catching up about our lives and I mentioned I had a funeral to attend this week. The person was 37 and very fit. He was my personal trainer and helped guide me in my weight loss journey. My friend asked if he had been vaccinated for Covid as the vaccinated die from Complications.
I tried to explain that she was jumping to conclusions based on lack of knowledge. However, since she worked in a medical office she saw things that she said were all caused by the vaccines. Thanks to articles like this one, I didn't convince her completely, but she admitted she didn't have enough facts to conclude that the vaccine gave my trainer a heart attack or was the cause of much of what she saw.
Thanks for covering this study, it's significant given we have few medications in the fight against Covid. What struck me: Smallish study, ages varied from 18-87, looks like it combined the unvaccinated and vaccinated instead of separating them out. Delta was the dominant variant and we're way passed it now. Some subjects didn't finish the full course of Paxlovid - so why even include them? And while it found that Paxlovid didn't significantly alleviate symptoms of Covid compared with the placebo, it did show a higher rate of severe events in the placebo group compared to the Paxlovid group. I still take lots of precautions to avoid Covid. But, should I get it, my bottom line is about staying out of the hospital, ICU, morgue or developing Long Covid. For me, the findings from this study aren't significant enough to prevent me from asking for a prescription.
Which leads me to this question: Can a provider deny a patient a prescription for Paxlovid - NEJM is held in high regard by many in the medical profession. Also, if I was still able to get a prescription, is it reasonable or even possible to get a 10 versus 5 days course of medication?
Among all the wicked smart ideas and syntheses in this post, I most appreciate the “dem apples“ reference to Matt Damon’s character in Goodwill Hunting?
I think he would be proud of your efforts here in the face of the New England Journal Ivory Tower 👌💪
Thanks but you need to return that soapbox to me now (lol). There were some serious rebuttals and glad you went to school on me. 😏 Sadly, with way too many PC reluctant to take the time for drug-drug interactions, renal function adjusted or just using the 'rebound' excuse, we really didn't need this. One peeve is as I've mentioned is using the same endpoint of symptoms alleviation as influenza and how often has it was said this isn't the flu. You saw the study on antibiotics didn't reduce LRTI cough and even increase it. Interesting to note that the end point was reached as 12 and 13 days that coincide with the inflammatory phase (mythically called 'rebound') of a biphasic disease. Oh dear, now I got to get off the soapbox. Good news is that is no change in the guideline per IDSA and HHS (NIH no longer updates theirs). https://aspr.hhs.gov/COVID-19/Treatments/Pages/Possible-Treatment-Options-for-COVID19.aspx
https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/#OverviewofCOVID-19TreatmentGuidelinesSummaryTable
Thank you for this deep dive. The NEJM study was available from clinical trials.gov since last September, so why publish it now? We have literally only one other oral medicine, don’t trash the more effective one. And symptom reduction is not the important end point.
Just like your invaluable “Covidlandia” construct, this is another wonderful contribution. I am so bummed that testtotreat ended 4/16, it was an option for those of us who would want treatment and worry about providers and pharmacists who may create barriers.
I forwarded this to my primary care physician's group practice, with the following preamble:
“I don't expect anyone to actually read the lengthy forwarded information below, but I want it on the record, in my file or chart or whatever it's called—and the next time I come down with COVID-19, I hope y'all will help me get Paxlovid for it without delay (or any static), unlike last time. I am at high risk for COVID-19 complications—I'm 66, and I'm an obese hypertensive diabetic, for crying out loud! I've had it twice already, and the risk only increases. I don't want to die of COVID-19. Thank you.”
Is there more room on the soapbox :) because as a patient this matters to me. Compared to the NEJM study, this cohort study from March 2023 published in JAMA Internal Medicine (Dr. Ziyad Al-Aly, who has studied Post Covid Complications (PCC) as much as anyone, being one of the authors), looked at almost 282K people with Covid that had at least 1 risk factor for progression to severe illness. It found Paxlovid used in the acute phase was associated with reduced risk of PCC including reduced risk in several organ systems, post–acute death and post–acute hospitalization. It included unvaccinated, vaccinated and boosted, as well as people with primary infection and reinfection, compared with 246K who had no treatment.
JAMA Intern Med. 2023;183(6):554-564. doi:10.1001/jamainternmed.2023.0743 Published online March 23, 2023. Corrected on January 16, 2024
Thank you. I knew we could count on you to provide context and thoughtful, clear analysis. This is very helpful.
To gauge your pt's risk for severe outcomes or for LC (or for benefitting from a mid-year boost), what factors do you consider beyond age, organ system issues, and immunocompromise? There's a long list of what I call second tier factors, and I can't discern how strong the connection/risk might be. I'd prefer one of your office post-its over the CDC's spotty guidance. Thanks so much for your work.
I had to share this comment from another site I cross posted to... I never heard of this, but it may prove prophetic, and either way it is a fascinating window into the machinations behind the science in some cases:
Commenter:
"4 years in the industry and 20 at FDA.
This looks like possible Life Cycle Management to me. [It may have a new name now. Renaming existing ideas is faster and cheaper than coming up with new ideas.]
To be absolutely clear, LCM is practiced industrywide. No company has a monopoly on it, all companies do it to a greater or lesser extent, because our regulations allow it. It has a limited number of fairly predictable moves, once you’ve seen how it works.
Note the affiliation of all the authors, and the study site.
Note the relatively small n and the ITT — sorry, intent to treat analysis — that guarantees a high dropout rate will strongly bias results against the drug. When people drop out after one dose, the last observation carried forward is not going to be friendly to the drug, unless they all dropped out because they were instantaneously healed. By the way, that kind of thing — early dropouts due to high efficacy — has actually been seen, and studies are then terminated early for ethical reasons [not leaving people on placebo when there is no further need for a placebo group].
Note the study population.
Note the publication in a top tier journal and the interesting tendency of the audience to “turn on” the drug uncritically. Are there “thought leaders” among those critics? I didn’t work in that area, I wouldn’t know the names. But I wouldn’t be surprised if there are.
Based on prior experience with how LCM works, I will be quite surprised if we don’t see press releases about a theoretical successor drug soon. They may even already be out there.
I’d guess there might be requests for fast track development and then for priority review. And if I were a betting woman, I’d bet on requests for acceptance of one large Phase 2 study performed at two sites in lieu of a Phase III study.
Non-US sites may be used. It’s obnoxious to send inspectors out to them. And studies conducted entirely outside the US are not generally registered with clinicaltrials.gov. clinicaltrials.gov/...
If LCM works as intended the new product will also cost much more than the original treatment, which will be withdrawn from the market shortly after the successor is approved, for “business reasons”.
Again, these are standard LCM type moves industrywide nowadays. Keep that in mind.
Also, one can reconstruct the trajectory I’ve predicted by looking at a company’s press releases, blurbs about new drugs in development that appear in the trade press, and, once approved, the clinical trials section of the package insert. Companies brag about fast track development and priority review, so the press releases will usually confirm if these happen. Publications related to the pivotal trials will indicate study sites. Thus, none of these predictions impinges on anything that could be considered trade secret.
The next link talks about what an interested reader can glean from the clinical trials section of an approved drug’s package insert… www.pharmacytimes.com/…
And once more I will reiterate: this is standard operating procedure. I personally am no fan, since the time pressures involved do mean that problems are not always caught during the trial stage. Sometimes a drug will be taken off the market post approval because the smaller, faster studies did not include enough people to detect a particular side effect.
But this is how drug development unfolds in the US nowadays."
Thank you very much, Ryan. At 86, there are good days, and not-so-good days. It is what it is. Covid has changed the trajectory of ALL our lives. I appreciate greatly your time and effort in gathering and giving this information. I only had Covid one time, not very seriously, but the potential for serious impact cannot be denied. I am extremely grateful for your sound and sane reporting.
Thank you for doing this. I just spoke with a colleague who's 79-year-old husband was talked out of Paxlovid by his primary doc because of rebound and that it can cause long covid (!?). Now it sounds like he's developing neurological consequences to having had covid.... I will be sharing your article with many people.