Uncuriouser and Uncuriouser...

Or, A Pharma Rep Brings Lasagna and Hard Truths About Modern Medicine

For the first time in my life, I was looking forward to a meeting. Even stranger, the object of my anticipation was a lunch with a Big Pharma rep. I usually go to great lengths to avoid meetings in general, and meetings with drug sales reps in particular, so what gives? It wasn’t the food - with apologies to our beloved Italian readership, I’m not a lasagna guy. Honestly, I was genuinely excited about the promise of a new medicine!

One of the main reasons I never took the pediatric Covid panic seriously is that I have up close and personal experience with a truly serious pediatric respiratory illness: RSV. RSV is no joke, it’s no media manufactured hysteria. I still have vivid memories of a terrible RSV season from my training. Our entire children’s hospital was full of sick babies, but more sick ones just kept coming. We ran out of beds and had to take over a floor of the adult hospital next door! I’ve never worked so hard in my life or seen so many really sick babies. Yet it was no national story, not even a local news item, nobody locked down anything, nobody set up mask mandates. It was considered a normal winter and life went on. To go from that nonchalance to mass toddler masking and year-long school shutdowns over an illness far less dangerous to kids than RSV… I still can’t believe it happened.

All of which goes to say that if there were a real good, “safe and effective” medicine to protect babies from RSV, I would be thrilled about it! I’ll go so far as to say that such a treatment would probably be one of the greatest pediatric medical innovations of all time.

Now you can understand why, for the last couple months, I’ve had the date of our drug rep lunch meeting circled: she was coming to tell us about just such a miracle drug!

But is it the real deal, or fool’s gold? The study the FDA relied on to grant approval is… problematic. It was very small (the trial stopped halfway through due to, you guessed it, Covid, and so only had half the patients they had initially planned, observed for half the time…the FDA didn’t care), it was opaque (given the study was so small and underpowered, they should at least have given more info about the few patients and their situations, but they didn’t, so there’s no way to know if they’re at all like our patients… the FDA didn’t care), and it had all the usual unconventional endpoint switcheroos and statistical sleight of hand we’ve all now come to expect from pharma studies (the FDA didn’t care). Oh, and did I mention way more babies died in the experimental arm than the placebo arm? That’s right, in a study designed to demonstrate that this medicine will save your baby from a potentially deadly RSV infection… a statistically disproportionate number of deaths were found in the babies who took the medicine. Did the FDA care? Need you even ask?

Now, to be clear, more babies dying in the treatment arm doesn’t *necessarily* mean the drug is deadly. Remember, it was a very small study. So one kid gets hit by a car in the treatment arm - as did apparently happen here - and all the numbers get skewed. Now, we know that if a person with Covid gets hit by a car, that is clearly judged a Covid death by our public health leaders. But since I’m not a corrupt, power-hungry psychopath,  I would never presume that getting hit by a car is a real side effect of any RSV medication. The whole reason to do a large randomized study is so you don’t have to worry about accidents like that, you have enough patients that freak car accidents don’t skew your numbers. But if you take shortcuts and use a tiny study and that study *has significantly more people dying in the treatment arm,* you can’t just handwave about traffic safety and move on.

Importantly, far from all the extra deaths were car related. Several were unexplained, sudden deaths. Could they be totally unrelated to the treatment? Sure! But how can we know that? We only know what we have in front of us, and if you were in such a hurry to make your zillion dollar pay day that you couldn’t be bothered to recruit more than a few hundred babies from war zones and developing nations (seriously, I know our health system has flaws of its own, but can we seriously generalize to America from studies done on babies in Ukraine and South Africa??), I’m sorry, I don’t know what to tell you, the evidence isn’t there. But who am I to advise such executives? They must know what they’re doing - the FDA certainly approved of their methods.

Given the limitations of the study, and my strong desire to be reassured about them as I desperately want a good RSV medicine for my kiddos, I was so excited to ask the drug rep some questions.

Her visit to our clinic was shocking. This is no rookie, she is an experienced professional, I think she said she’d been doing this for 18 years. I want to emphasize that she was very kind and friendly and nothing I am saying should be taken as an attack on her as a person or lasagna as a dish. Yet not a word of her presentation was about the above study or the details about the safety and efficacy of the drug. She just raved about how easy the medicine was to administer, how little paperwork was involved, and other trivialities. My favorite part was when she emphasized that the treatment was not a vaccine, and that’s a good thing, “because we all know vaccines have side effects!” I guess pharma will admit it, in the right circumstances…

Perhaps you’ve noticed, if you happen to possess a pulse, that we are at an all-time low when it comes to public trust in institutions. Unless you’ve been shipwrecked the past couple years you realize that fewer and fewer people trust public health authorities, the FDA, and anything novel-vaccine-related in particular. So, surely, if your job is to be a rep for a drug company unveiling a new kind of ‘immunization,’ you’re going to be prepared for some pushback, right? I’m not even asking for honesty, only *preparation* - you can be like Fauci and blatantly lie about the issue, but at least have a set of those lies ready to go, you know?

But, unless this rep is the best actress in the world, not only was she unprepared for gentle questioning, she was blindsided. She could not even begin to answer any question I or my colleagues posed. The way she explained her role, she had no familiarity with the study details or the science, but she promised to try and get someone else at the company, on the “science” side, to get back to us to answer our technical questions - if we filled out and signed a form! See below:

Sure, you can ask questions - if you tell us where to send the hit squads…

Consider what the rep’s surprise implies. I mean, how could she be so experienced at her job if she spent every meeting inelegantly dodging obvious questions? No, the truth is far more frightening, I suspect: I think our clinic might be the only one she’s encountered that even asked a skeptical question! I mean, what other explanation is there?

Based on her genuine surprise at being asked about study size and study deaths, it seems that every other clinic in her large sales area simply accepts the FDA’s word at face value, asks no serious questions, and cares only about the car salesman bells and whistles (and lasagna). Oh, did I mention ours is the only clinic in the area that is still a small, family-run business? Every single other one that used to be independent has been bought out by a big corporate hospital system. Wonder if that’s relevant to any of your experiences with your pediatrician the last few years…

So, what do I think about the miracle new RSV drug? I honestly don’t know. I hope it works and is safe! I would love to have a large, well done, randomized trial showing that it does - preferably in some non-war-torn developed nations. I don’t want sick babies to die preventable deaths. Yet considering that the FDA approved this drug without evidence that it does prevent such deaths, and that my few colleagues and I are apparently the only doctors in the neighborhood to care, my greater concern right now is for the death of medicine itself.

*Here endeth the main post, thank you for reading. Some more study ranting now follows, please forgive me:

Two mini rants, variations on a theme. The babies most at risk of dying from RSV are the more ‘sickly’ babies (the ones with “comorbidities” as we all call them these days). So the focus of such a trial ought to be on these high-risk kids, as they are the ones most likely to be saved by this drug. Well…

A) When it comes to explaining away the deaths in the treatment arm, the study discounts several of the deaths because they are in very sickly kids. As in, sure, they died, but let’s face it, they were on death’s door anyways, so no biggie. See for instance page 39: “Another two subjects died of lower respiratory tract infections. Of these two subjects, one had underlying severe protein calorie malnutrition and the other had multiple underlying conditions. […] Both deaths were likely related to underlying conditions rather than to nirsevimab.” But the whole selling point of the drug, the whole purpose of it, is to protect those vulnerable kiddos! You can’t roll out a drug aimed at high-risk kids while simultaneously pooh-pooing their deaths since they’re so sickly. It’s great that no healthy, strong 5 year olds are going to die from your drug, but they’re not going to be given the drug in the first place since they’re so strong and healthy they’re not worried about RSV…

If your plan is to ignore the outcome of your drug in kids with multiple underlying conditions, why did you enroll them in the study in the first place? I can understand with everything going on in Ukraine right now it’s probably hard to find volunteers, maybe that’s a reason to do the study in, I don’t know, America?

B) The company did enroll a cohort of high risk kids to test the safety of the drug. But in that cohort they explicitly say they did not test its efficacy. Why? Because they tested the efficacy on the healthy kids, and they figure, well, kids are kids, so if it works in healthy kids it’ll work in sickly ones, too, right? See page 29:

“Extrapolation of efficacy was considered appropriate because:

1. The pathophysiology of RSV infection is sufficiently similar between infants with and without certain medical comorbidities.

2. The mechanism of action, and the viral protein target of nirsevimab is the same regardless of the host conditions.

3. The response to prevention is expected to be similar between infants with and without additional medical comorbidities.”

Well, maybe. But isn’t the whole point of the study to see if it works in the most vulnerable? You can’t just assume your conclusion. Next thing you know you’re going to argue something insane like stating that simple logical extrapolation proves that Covid shots protect babies from hospitalization because they increase antibody levels in non-babies. Oh, wait… Again, this isn’t how any of this works!

Both of these issues would’ve been moot had they designed a large enough study. As it is, now we will never really know… sound familiar?