The FDA drug approval process is known to be a lengthy and rigorous one. But the FDA-approved ingredient phenylephrine — found in common cold medicines like Sudafed, Mucinex, and NyQuil — was recently found to be no better than a placebo. Phenylephrine has been on store shelves for nearly 90 years. How could that happen?
In this episode of Tiny Matters, Sam and Deboki are joined by none other than Deboki's dad, Deb Chakravarti. Deb is a professor with years of industry experience and the current director of the York College FDA Partnership. He helps dissect the FDA's recent findings and how its history and ever-evolving role in the pharmaceutical industry contributed to phenylephrine being used in oral cold medicines for so long.
Deb, Deboki and Sam also unpack pharmaceutical ethics cases, like thalidomide in the 1950s and 60s, and the case of Vioxx in the early 2000s, which led to tens of thousands of deaths.
Sam and Deboki cap off the episode with tiny show and tells about how the nose is really 2 noses (!) and the story of a new, ingestible, vitamin-sized capsule that could protect people from dying of an opioid overdose, sleep apnea, or other conditions that depress breathing.
Transcript of this Episode
Deboki Chakravarti: Hey Tiny Matters listeners, before we hop into today’s episode Sam and I want to share another podcast you might be interested in — it’s called Science Sessions and it’s produced by the Proceedings of the National Academy of Sciences or PNAS.
Sam Jones: Science Sessions provides an opportunity to learn about the exciting work of cutting-edge scientific researchers. Whether exploring the extraordinary hunting abilities and adaptations of spiders or unraveling the nature-inspired design of robots capable of mimicking plants and animals, each episode promises a memorable tour through the scientific trenches.
You can find and subscribe to PNAS Science Sessions on popular podcast platforms like Apple Podcasts, Spotify, and Google Podcasts.
Deboki: Sam, I don’t know about you, but I feel like part of adulthood has involved realizing that all of my friends and I have very specific attachments to whatever cold medicine we used when we grew up. Like I lived in a Robitussin household, but when I got to college, I had friends who swore by NyQuil or Sudafed or Mucinex or something else.
Sam: That’s so funny. I never really thought about it, but we were definitely a NyQuil household. When I was really little I was all about that Children’s Dimetapp.
Deboki: And there’s a good chance that your preferred cold medicine contains a decongestant called phenylephrine. In fact, in 2022, at least 250 products containing phenylephrine were sold in the US, and they brought in around $1.8 billion in sales. But in September of this year, an advisory panel for the Food and Drug Administration released a report that said that oral phenylephrine—this incredibly popular ingredient—was no better than a placebo.
Welcome to Tiny Matters. I’m Deboki Chakravarti, and I’m joined by my co-host Sam Jones.
Sam: The results of the FDA’s advisory committee’s review of phenylephrine only came out a few months ago. But this is an ingredient that has been on the market for nearly 90 years.
So today, Deboki and I are going to dig into why phenylephrine was approved in the first place. And that means talking through how the FDA works, the history that got us to the modern day drug approval process, and how that history meant that phenylephrine was able to get past the current FDA guardrails. And of course we’ll talk about how scientists managed to finally get the FDA to release its report on oral phenylephrine’s efficacy… or lack thereof.
Deboki: And we’re going to do it all with the help of a special guest.
Deb Chakravarti: I am Deb Chakravarti. I am a professor in the City University of New York, York College Department of Chemistry. I'm also the director of the York College FDA partnership.
Deboki: For those of you listening closely, you might notice that our guest’s name sounds a lot like my name. And that’s because he’s my dad. He used to work in the pharmaceutical industry, but he is a total professor at heart, which means that I’ve heard a lot of stories about drugs and the FDA from him. So when I heard about the phenylephrine news, I knew I wanted to ask him to explain more about what happened, and I knew that he’d want to talk about it because this is a subject he’s really passionate about and… he loves to talk.
Sam: So what does it take for a drug to become an FDA-approved drug? Over the past few years, the process has been in the news quite a bit thanks to COVID and the public wanting to know that the vaccines and drugs being released were both safe and effective.
But COVID was also a unique situation where, although the necessary precautions were taken, things needed to move more quickly than they typically do to combat a rapidly spreading, highly contagious virus. So today we’re going to talk more broadly about how drug approvals usually work. Just know that there are sometimes circumstances that would lead to variations on this.
Deboki: Before a drug even gets to the point where it can be evaluated by the FDA, there’s a lot of preclinical work in lab models like mice that has to happen to demonstrate why the company behind the drug wants to further test it. And when that’s done, the company will submit an application to the FDA describing how they plan to go about doing clinical trials in humans. Overall, clinical trials come in four phases.
Deb Chakravarti: So phase one basically looks with a small group of people, safety and dosage of the drug. And that's usually conducted in healthy volunteers. The goal is to determine what the drug's most frequent side effects are and if it is safe or not basically. And typically it'll use like 20 to 100 people and it takes one to two years to do that. Once everything looks good at the end of phase one, it goes to phase two, they look for efficacy and safety. Previously it was only safety.
So the main question in phase two is does the drug work as a drug? It might be safe, but does it work? So typically phase two with the drugs go with a hundred to 300 people and it takes again one to two years.
And if that is all successful, there's a discussion with the FDA and it goes to phase three — efficacy and safety with side effects. And this time typically involving a thousand to 3,000 people. There might be more different study groups defined at this point to look into different genetic backgrounds. And this one takes a little longer, about two to three years.
Sam: If everything goes well in a phase three clinical trial, the company can then move on to what’s known as the New Drug Application or NDA, not to be confused with a non-disclosure agreement. If the NDA gets approved, they can start marketing the drug in the US. To sell outside the US, companies have to work within those countries’ laws.
Deboki: But wait, we said there were four phases of clinical trials, so how are companies selling the drug after only three?
Deb Chakravarti: Once it enters the market, that is when the biggest clinical trial starts. And people do not often recognize this because clinical trials in phase one, two and three may not accurately reflect the real world because at this point it is going from the thousand to 3,000 people in phase three to hundreds of thousands to millions of people. So post-marketing studies gather additional information about safety, efficacy and optimal use of the drugs.
Deboki: Safety and efficacy are obvious things we want in our medicines. We want our drugs to be safe, and we also want to know that they’re going to do the thing they claim to do. But it’s actually taken some time for both safety and efficacy to become fully part of the FDA mission.
Sam: Way back in episode 14, Deboki and I laid out the history of the FDA when talking about preservatives in foods, drugs and cosmetics. I recommend revisiting that episode if you want to learn more about how the FDA has evolved. But here’s a very quick summary of what you need to know for today.
In 1906, after the publication of Upton Sinclair’s book The Jungle exposed the horrific conditions of the meat-packing industry in the US and triggered a loud public outcry, Congress passed the Pure Food and Drug Act, which laid the groundwork for the creation of the FDA. The act banned the sale of food and drugs that were either misbranded or adulterated.
Deb Chakravarti: And this was replaced by the Food, Drug and Cosmetic Act, passed by US Congress in 1938. And this still continues to be the major basis of FDA's regulatory authorities. And this required new drugs to be safe.
Sam: Safe…but not necessarily effective. That just wasn’t in the purview at the time. But over the next few decades, Congress began to add more regulations. In 1951, the Durham-Humphrey Amendment created a delineation between prescription drugs and over-the-counter drugs, which are also sometimes called OTC drugs. But the requirement that drugs be proven effective didn’t come until the 1960s, when a famous case related to drug safety provided support for major reforms in how the government approached regulating the pharmaceutical industry.
Deboki: In 1960, a woman named Frances Oldham Kelsey began working at the FDA as a medical officer reviewing applications for new drugs. And one of her first application reviews was for a drug that was already being used in a number of countries around the world. The drug was called thalidomide.
Through the 1950s and 1960s, thalidomide was given to pregnant women as a treatment for morning sickness. The brand name of the drug was Kevadon, and its manufacturer — the company William S. Merrell — was looking to be able to sell it in the US too. But some research raised red flags for Frances, so she asked for more data.
Deb Chakravarti: In one published report, some patients had some sort of loss of sensation or something in their toes or something and she didn't like this. And based on that, she wanted more data to be generated.
Dr. Frances Oldham Kelsey took a very bold stance against inadequate testing and corporate pressure. Corporate pressure was enormously on her.
Sam: Merrell continued to send data about thalidomide, and Frances continued to find it lacking. But within a year, researchers in other countries began to identify clusters of severe birth defects that were linked to the drug. Thankfully, thalidomide was never approved in the US.
Deboki: Frances’s work ended up not just sparing countless people the pain of thalidomide’s side effects. It also ended up providing support for a new set of amendments in 1962 called the Kefauver-Harris Amendments that expanded the FDA’s powers. They could now demand that a drug not just be proven safe, but also effective. These amendments would end up forming the foundation for the phased clinical trial system that we know today.
Sam: So the FDA was tasked with proving drugs are safe in 1938, then tasked with proving drugs are safe and effective in 1962. But what about all the drugs in between 1938 and 1962? Here’s where we get to our cold medicines.
Deb Chakravarti: We all take oral cold medications and they often have three different active pharmaceutical ingredients, which are typically called APIs in them. One of them is a cough suppressant like dextromethorphan hydrobromide. Another, the second one is usually an expectorant like guaifenesin that is to loosen the phlegm or congestion in the chest and throat. And third part is a nasal decongestant for the stuffy nose that supposedly shrinks blood vessels in the nasal passages.
Deboki: There are two nasal decongestants that you can get without a prescription: phenylephrine and pseudoephedrine. But in the 2000s, pseudoephedrine was moved behind the counter due to concerns about its use to make methamphetamine. You could still get the drug without a prescription, but you would have to show an ID and ask a pharmacist to get it for you.
And for drug manufacturers, that wasn’t great. I can’t speak for all customers, but I will totally make decisions based on minor inconveniences like being able to pick something from a shelf versus having to ask someone to get it for me.
Sam: Totally. And so phenylephrine became a more popular ingredient. Plus, it had been around for a while. It was patented in 1933 and used in drugs starting in 1938. If it’s been around that long and even got past the Kefauver-Harris Amendment in 1962, then it has to be pretty reliable, right? Well, sort of.
Deboki: With the passage of the Kefauver-Harris amendment, the FDA suddenly had a whole lot of drugs on their hands that they had already deemed safe…but not necessarily effective. So to deal with that challenge, the FDA came up with a process still used today called OTC drug monographs.
Deb Chakravarti: OTC drug monographs are a kind of recipe books. They cover acceptable ingredients, doses, formulations, labeling, testing. The products conforming to a monogram may be marketed without FDA approval as long as you follow the cookbook. While those that do not must undergo separate review and approval through the new drug process.
Sam: The monographs cover the use of the drug, the dosage, how you’re administering it, and a number of other requirements. As Deb said, monographs are like a cookbook. And as long as you stick to a recipe that’s FDA approved, you’re good. You don’t need to go through the NDA process.
The goal for an over-the-counter or OTC drug is to achieve what’s called GRASE status, that’s G-R-A-S-E, which stands for “generally recognized as safe and effective.”
And remember that the FDA is not just focused on drugs, so GRASE ingredients are found in all sorts of products we use every day. Like salicylic acid in skincare, or titanium dioxide in sunscreen.
Deb Chakravarti: So in 1972 FDA established the OTC drug review process to evaluate the safety, effectiveness of hundreds and thousands of OTC drug products that were on the market at that time. At that time dating back to early seventies, both the compounds phenylephrine and pseudoephedrine were evaluated under the OTC drug review.
Now FDA is very aware that this GRASE status for OTC monograph ingredients relies in many of these instances on data which was generated 30 to 50 years ago and that were not derived from what are currently considered state-of-the-art clinical studies. So our today's standards are obviously a lot different than what was 30 to 50 years ago.
Sam: And pharmacists had their doubts about phenylephrine. Some were even calling into the University of Florida Drug Information and Pharmacy Resource Center hotline, which healthcare professionals across Florida could call with questions about drugs. And they were calling to ask whether this widely used cold medicine ingredient actually worked.
One of the doctors running the hotline was Randy C. Hatton, and when he looked into the research, he found that a colleague at the University of Florida named Leslie Hendeles was also skeptical that phenylephrine was effective when given to patients orally.
Deboki: They re-examined data from the 1960s and 1970s and found that the drug wasn’t any better than a placebo. But while their research kept turning up signs that phenylephrine was not an effective oral medication, it took a while to get the FDA to listen to them.
At first, the FDA reiterated their approval of phenylephrine from the 1970s. It took a lot of work on the part of these pharmacists to gather data from older studies and be on the lookout for new studies related to phenylephrine. But eventually, an FDA advisory committee called for more data, which was followed by multiple large clinical trials and lots of data for the committee to look over.
Deb Chakravarti: So from the data they presented, it turns out that this was no better than a placebo or a sugar pill.
Deboki: This only relates to the oral form of phenylephrine. There’s also a nasal spray form, but that’s not affected at all by this decision because it seems like phenylephrine does work when it’s sprayed into the nose. And phenylephrine is used for other purposes, like it might be added during anesthesia to maintain blood pressure. Those uses are not affected by this decision either.
Also, there is still a process to go through that will determine whether phenylephrine will have its GRASE status removed, at which point the FDA has said it would work with manufacturers to reformulate their products. In a statement about their stance on phenylephrine, the FDA noted that there are no concerns about safety when it comes to using oral phenylephrine at the recommended dose.
In the meantime, CVS has already said that it is removing oral cold medicines that only have phenylephrine as the active ingredient.
Sam: So this was a case of efficacy, but what about that other thing we definitely need from our drugs? Safety.
Deb told us that when drugs that have been approved are later found unsafe, they will often end up being reintroduced with additional warnings or restrictions added. And generally, the safety issue he’s seen most frequently tends to be liver toxicity, which can be very dangerous.
Deboki: He also told us about a drug called rofecoxib, which was sold by Merck as Vioxx. The drug was approved in 1999, and then recalled five years later.
Deb Chakravarti: It's a non-steroidal anti-inflammatory drug. Normal NSAIDs we use are aspirin Advil. But NSAIDs generally work with both of this form of this enzyme called cyclooxygenase one and two.
Sam: Cyclooxygenase enzymes one and two are also known as COX-1 and COX-2, and they’re involved in inflammation. So some common NSAIDs like ibuprofen work by targeting both of these enzymes. But COX-1 enzymes are also involved in protecting your stomach lining and intestinal tract from the acids in your digestive system, so sometimes people experience ulcers and stomach pain when they take NSAIDs, which is why some doctors may recommend taking NSAIDs with food.
So the idea behind Vioxx was to specifically target COX-2 enzymes, alleviating the risks associated with COX-1 enzymes and reducing gastrointestinal side effects. However, there were concerns that the drug caused heart problems.
Deboki: And these heart problems showed up in safety studies, but Merck obscured the data when submitting results to the New England Journal of Medicine — even excluding some of the heart attacks that had occurred in one of their trials. When they released Vioxx to the market, Merck made an annual revenue of $2.5 billion from the drug. But as researchers continued studying the drug, they found a significant number of heart attacks.
Merck eventually recalled the drug, and paid $4.85 billion into a settlement fund to deal with lawsuits related to Vioxx. There are different estimates for how many people died because of the drug, but the lower end is still baffling, at somewhere around 38,000 people.
Deb Chakravarti: This is a case study I often do in pharmaceutical ethics classes.
Deboki with Deb Chakravarti: When you're teaching it in pharmaceutical ethics classes, what are you hoping your students will learn from the case study?
Deb Chakravarti: To really not be retroactive but be proactive because a lot of the changes in US drug laws have been after something has happened. But if you have some sort of futuristic idea that something might be, then act on it and do not try to protect anybody else, not even the pharma company.
Deboki with Deb Chakravarti: Well, that probably leads us well into our next question, which is that for us as consumers, we're relying on the FDA to tell us about our medications and which ones are safe and effective. So when stories like this phenylephrine story come up, how should we process this in terms of trusting the process, the FDA, the pharmaceutical companies?
Deb Chakravarti: One very important thing for all of us to consider is the importance of reporting suspected drug adverse effects. And since 1969, there's a reporting system, the Adverse Effect Reporting System or AERS that has provided FDA with drug surveillance information and that has supported regulatory decision risk assessments about the safety of marketed drugs. So the FDA advisory panel's review of the efficacy of phenylephrine that considered the data collected over so many years, over 50 years, is very encouraging to see that these things do take place even if it takes time some time to do that.
Deboki: It’s hard when you’ve got a stuffy nose, or maybe someone in your family has a really bad cold, and you’re staring down the aisle with all those colorful packages, and you just want to pick something that works…and now you also have to remember that maybe this one ingredient doesn’t actually work.
But the thing I’m taking from talking to my dad about all this is that the FDA is constantly evolving and with that evolution, improving. It changed a lot even within the first few decades of its existence, and it’s changed even more in the decades since. And all along the way, the effectiveness of the FDA has come down to people. Some of them have been inside the FDA, some of them have challenged it from the outside. But their common trait is that they haven’t taken any label for granted. Instead, they combined their skepticism with persistent, careful work to keep the rest of us safe.
I will go first for this Tiny Show and Tell. This is one of those Tiny Show and Tells where the article is actually very related to what we talked about in this episode. This is a recent article I found in The Atlantic called Everything I Thought I Knew About Nasal Congestion is Wrong.
It's by Sarah Zhang and this article is about the idea that our nose is not just one nose, it's actually two noses. So if you look inside the nose, each nostril goes to its own nasal cavity and those cavities are two distinct organs that don't directly connect to each other, which I guess makes sense, I just didn't really think of it that way. I just kind of assumed that somehow they very directly connect.
This is not just me having an inaccurate picture of our nose, it means that also the way our nose works is very connected to the fact that there are two distinct cavities going on. And it's really dynamic as well. The tissue in our nose swells up with blood. When we get a stuffy nose, it might feel like it's because there's mucus back there. That's part of what's going on, but a lot of what's going on is the swelling of that tissue with blood.
That's why even when you blow your nose or you sneeze, you can't completely get rid of that stuffy feeling, because all of that is actually tissue. It's not just that mucus that's there. And so, that's why decongestants like, theoretically, phenylephrine ... The way it was supposed to work, it's supposed to shrink those blood vessels in the nose and ease up on that swelling. But the additional step to this that was super fascinating to me is that there is a cycle going on.
There's a swelling and unswelling in that tissue that's regularly happening. It's not just about being sick. And it cycles between both sides. One side will open up and the other side will get partially congested, and this is somehow controlled by receptors under the arm, which is something that people have looked at as a way to be able to control the nasal cycle. I don't know quite how that works, it was just a really interesting thing there.
Also, then the question is, "Why is our nose set up this way?" We're not the only animals that have this. Cats and dogs have it too. We don't know exactly what the purpose is, but there's one hypothesis is that it's actually a way to protect us from pathogens. One thing that people notice is that as the tissue swelling goes down on one side of the nose, there's plasma full of antibodies that will then go into the inner lining. This might be a refresh of that antibody-filled plasma into one side of your nose.
It also might be a way to regulate the temperature in different sides of your nose, so as one side gets more congested, it also will get warmer, and that will make it less hospitable to viruses. I just thought that was really interesting, because I did not realize ... I think of the nose as sort of complicated, because there's olfaction going on and stuff, but breathing I kind of take for granted.
Sam: It is really interesting and complicated. And it's funny, because I studied the olfactory system, but through thinking about smell. And so, I never thought about congestion, what's actually happening in the nose. That's so interesting.
Deboki: The nose is cool. I've been watching a lot of Botched recently, and so I've been learning a lot about how important people's noses are. Again, it makes sense. I know that my nose is important for breathing, but it is kind of ... In the horrific way that having terrible surgery that's gone wrong on you, it is interesting to understand how important having both these nasal cavities is to our breathing.
Sam: For my Tiny Show and Tell, I'm going to tell you about this cool new device that researchers have developed. It looks like a very standard vitamin capsule or medicine capsule, and it actually can safely monitor vital signs like breathing and heart rate from inside the person who ingests it. This pill detects a heart rate and respiratory rate. Both are measured using this thing called an accelerometer that will actually measure distinct vibrations in the gastrointestinal tract.
For example, to measure heart rate, it's looking for these really small, short movements. The idea behind the development of this tool was actually to provide accessible care for people who are at risk of opioid overdose and for people with conditions like sleep apnea that could cause them to stop breathing.
The effectiveness of the pill to detect opioid overdose specifically, it was actually tested in pigs who were given fentanyl, and then had the overdose reversed with Naloxone, aka Narcan. Part of what appealed to me about this new potential piece of tech is that it relates back to the episode that we did last week on the opioid crisis.
And then, in humans, the pill was tested in people with sleep apnea. Although people with sleep apnea can also stop breathing involuntarily, it does seem like the ultimate goal of this is to really help people who are at risk of opioid overdose. Because actually, in 2022, it's estimated that over 109,000 people died of an opioid overdose just in the United States, which is very scary.
And so, I thought this was really cool. These are early days, so the researchers are now actively working on modifications for the device to stick around longer. Like I said, it's ingested. Within a few days, it is naturally excreted. Eventually, they'd like to modify it to stick around for longer, but also to release Narcan or another opioid reversal drug once the overdose symptoms are detected, which I thought was cool.
All I could think when I was reading about this was that I want to know what people in the harm reduction space, like Hansel Tookes, who we talked with for the last episode, what they think of this kind of thing. Would someone who is an opioid user be interested in having one of these devices? Would this be something that people would actually use? Because technology is interesting, but if people actually wouldn't use it, then what's the point?
Deboki: Totally. I'm so curious about what the implementation would look like if they continue pursuing this and it continues working well.
Sam: For sure.
Deboki: Did they talk about other potential applications? Or is this their primary focus?
Sam: Primary focus would be overdose or preventing overdose deaths. And then, it seems like the secondary focus is sleep apnea, so people who involuntarily stop breathing while they're sleeping, which a lot of people don't even know they have.
Deboki: Right. That's so interesting.
Sam: Thanks for tuning in to this week’s episode of Tiny Matters, a production of the American Chemical Society.
Deboki: This week’s script was written by me and was edited by Michael David and by Sam Jones, who is also our executive producer. It was fact-checked by Michelle Boucher. Also, my mom, Bulbul Chakravarti, helped with this episode. She’s a professor as well and teaches about the history of the FDA, but alas, she did not want to be interviewed for the podcast.
The Tiny Matters theme and episode sound design are by Michael Simonelli and the Charts & Leisure team.
Sam: Thanks so much to Deboki’s dad, Deb Chakravarti, for joining us. If you have thoughts, questions, ideas about future Tiny Matters episodes, send us an email at tinymatters@acs.org. You can find me on social at samjscience.
Deboki: And you can find me at okidokiboki. See you next time.
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