A held a hearing to review a drug previously approved for the treatment of metastatic breast cancer.

The hearing was fraught with concerns over the drug's safety, competing with cancer patients who felt they were alive because of the drug.

Today's guest was on the panel-receiving testimony, and weighed what he heard against the long history of the FDA, to make sure drugs are safe and effective.

He's Dr. Mikkael A. Sekeres, this week on "Story in the Public Square".

(upbeat relaxing music) (upbeat relaxing music continues) (upbeat relaxing music fades out) Hello, and welcome to "Story in the Public Square", where storytelling meets public affairs.

I'm Jim Ludes from the Pell Center at Salve Regina University.

- And I'm G. Wayne Miller, also with Salve's Pell Center.

- And our guest this week is Dr. Mikkael Sekeres M.D, an oncologist at the University of Miami School of Medicine.

He's also the author of a new book, "Drugs and the FDA".

Mikkael, thank you so much for being with us this week.

- Well, gee whiz, thank you for having me.

What a privilege.

- Well, you know, I really enjoyed your book, and I learned a lot about the history of the FDA, and I learned a lot about the way the FDA approves drugs.

But why did you write this book in particular?

- Well, what sparked this was an experience a few years ago.

I served on the Oncologic Drugs Advisory Committee of the FDA.

That's the committee, when you read in the Providence Journal, for example, that an FDA committee today voted to approve a drug, that was our committee focused specifically on cancer drugs.

I was on that committee for five years and chaired it for two years, and realized that nobody had really written about the experience of how the FDA approves drugs rapidly, what they call accelerated approval, to get drugs on the market as quickly as possible for people who have life-threatening illnesses.

- Well, and you also provide a really sort of important history about why we even have an FDA.

So, let's go back a century or more into the origins of the FDA, and why do we even have such an agency in the first place?

- Yeah, that's a great question.

And that was one of the fun parts about writing this book, is trying to figure out what events led to the culmination of accelerated approval and how we approve cancer drugs today.

And then, if you go way back to the 19th century, there were no regulations on how drugs were used and how they were marketed and distributed.

So, there were some drugs with dubious names like Hamlin's Wizard Oil, that were not exactly the medicinal panaceas they claimed to be.

In fact, this drug advertised itself as a wondrous cure for ailments ranging from toothache, rheumatism, laying back, hydrophobia, pneumonia, all the way to cancer.

It even had a short slogan that bragged, "There is no sore it will not heal, no pain it will not subdue."

So, these drugs were distributed across the country, really with no regulation at all.

It wasn't until 1902 that the first steps towards regulation occurred.

And one of the premises of this book is that it took a series of tragedies for the government to react and put into place what we now recognize is how the FDA approved drugs.

In 1902, children in St. Louis and in Camden, New Jersey, got sick with smallpox and diptheria.

So, they were given vaccines to treat these infections, but unfortunately the vaccines themselves were contaminated with another deadly toxin, tetanus.

So, unfortunately, these kids died.

In response, Congress passed the Biologics Control Act, and soon after, the Pure Food and Drugs Act.

So, this led to the first steps towards what we would now recognize as an FDA.

But this legislation really just said that bottles of drugs that had a description on the bottle had to accurately describe what was in the bottle.

That's all the legislation said.

So, it was really a truth-in-advertising legislation as opposed to legislation that focused on drug safety and efficacy.

- So, Mikkael, the FDA obviously has responsibility for drugs, but also for many other products.

It's not simply drugs.

Can you talk about some of the other products, consumer products that the FDA has regulatory authority over?

- Yeah, for sure.

So, I focus, in my book, on drugs because it's what I know.

Obviously, I'm a doctor, I'm an oncologist.

I specialize in treating people with leukemia, and I have a background in pharmacoepidemiology; so the epidemiology of drugs, side effects that drugs and how they're used.

The FDA is also, of course, responsible for food, it's responsible for cosmetics and it's responsible for devices.

So, if you think of how any of those are applied to the body or inserted into the body, the FDA is supposed to regulate that and make sure that they are safe.

Now, the efficacy part, so whether or not they work, is a slightly different story.

That is focused more on drugs, is more rigorous and focused on efficacy of drugs, and I think, to a lesser extent, on the efficacy of devices and on cosmetics.

- And it plays another major role.

And I think, you know, the lay person certainly saw this big time during the COVID pandemic, and that is getting accurate science-based information to the public.

Talk about that, 'cause that also is a... You know, you can have research, and you can have regulations, but if you don't get information to the public, you know, you're kind of shouting down a well.

Talk about the public service, as it were, aspect.

- Yeah, it's a fabulous question.

So, I think we were all frustrated with the communication we were receiving from authorities in the government, right when COVID was breaking, on what the right thing to do was.

I remember when COVID first broke and we were trying to figure out how to be safe around our patients who have leukemia, who have severely compromised immune systems.

And at the very beginning, we were focused much more on surfaces, on cleaning surfaces and making sure we had no contact with patients.

And every surface we cleaned, but we weren't masking yet.

Well, that changed, as it was recognized that COVID was more airborne, as opposed to something that lay in droplets on surfaces.

And then, we focused appropriately much more on masking.

And then, of course, we had the miracle development of these vaccines in really record-breaking time, something that saved hundreds of thousands of lives.

So, the communication that we heard, though, was changing in real time.

And that's the nature of science.

And I think, as scientists, we recognize when that happens.

When something kind of new and exciting breaks or new and devastating breaks, we know that the initial story may not be the final story, so we approach it with caution and appropriate suspicion.

I don't think the government, particularly the CDC, and to some extent, the FDA, took that same caution in how it explained things to the public.

And as a result, the public heard mixed messages, and that compromised the trust of the public.

And that's why part of the title of my book is its "Drugs and the FDA: Safety, Efficacy, and the Public's Trust".

And I do think that's a critical aspect of public agencies like the FDA, that they have to work on that communication to build trust in the public, so that everybody in America will trust that the medicine they're taking out of their cabinet is both safe and effective.

- Well, and Mikkael, you talk about safety and efficacy; that's a recurring theme throughout the book, and that wasn't always the case in the history of the FDA, As you put it, different tragedies got us to the point where it wasn't just about efficacy, it was also about safety.

Can you say a little bit about that?

- Yeah, so if we go back 100 years, the number-one killer at the time was infections.

People died of infections, right?

Nowadays, we think about that, and we laugh a little bit.

Really, people were dying of infections?

I thought people died of cancer and heart disease.

They didn't have that luxury to live that long back in the beginning even of the 20th century.

So, in the top 10 killers of people in the first 30, 40 years of the 20th century, infections were four of them.

So, a lot of companies were rushing to make new antibiotics, discover new antibiotics, and new ways that people could take them.

So, in the 1930s, the S. E. Massengill Company of Bristol, Tennessee, wanted to create a liquid form of the antibiotic sulfanilamide; something that would be more palatable, and also especially more palatable to children.

So, their chief chemist, a guy named Harold Cole Watkins, added substances to make the drug more ingestible, and that included things like raspberry extract, saccharin, caramel, and the sweet-tasting solvent diethylene glycol, what we would now call antifreeze; because at the time, there were no regulations.

There was no stipulation that a drug had to be safe or that it had to be tested for safety before it was distributed.

So, sure enough, in September of 1937, 240 gallons of this stuff were distributed across the country, and doctors began prescribing it regularly.

But then, over 100 people, 71 adults and 34 children, died from taking the tainted antibiotic.

And the FDA then had to react to this, and they sent out scores of employees of the FDA to try to retrieve every last ounce of that remaining antibiotic.

And there are these incredible stories of FDA agents going into alleys outside of pharmacies to recover the bottles that had a few drops of the liquid left, or even going to a small town in South Carolina where the tradition was that, when somebody died, you would bury their medicines into the ground on top of that grave.

And they recovered some of this sulfanilamide.

So all told, they were able to recover 234 gallons of this stuff, recall it, and that led to legislation eventually signed by Franklin Roosevelt to initiate the Food, Drug, and Cosmetic Act in June of 1938.

And for the very first time, that required that drugs be safe; not effective, they didn't have to work, it just had to be safe.

- So, Mikkael, the driving narrative of the book is the account of the FDA's trial for the drug, Avastin.

And you served on the jury.

Let's start with what is that drug, and what were its purported benefits, and why was there a trial?

- Great question.

So, Avastin, the brand name Bevacizumab, was a drug that was developed to treat metastatic breast cancer.

Now, it was brought onto the market under something called accelerated approval.

Let's go back briefly to the 1980s.

HIV and AIDS were sweeping the nation, and there were no treatments for people who had HIV or AIDS.

I remember I was in classical high school in Rhode Island in AP biology, where we first heard about the HIV and AIDS phenomenon.

So, there were patient advocates who were born from that, including those in the group Act Up, that really pushed the FDA and the government for a path to approve drugs quickly for people who had life-threatening illnesses like HIV or AIDS.

And in 1992, legislation was put into place where there was a pathway for drugs to be approved quickly before these massive trials had to be conducted, where patients were randomized to get the experimental drug or standard of care to demonstrate that the experimental drug was safer and more effective than the standard of care.

There were quicker paths, quicker studies that could be conducted for these drugs to get approved.

Eventually, this legislation that was born outta the HIV/AIDS movement was really co-opted by cancer.

And cancer became king, and the number one reason drugs received accelerated approval to get onto the market quickly.

The caveat of accelerated approval by the FDA is that a follow-up study has to be conducted that really proves that the drug is safe and effective.

So, a drug gets onto the market quickly with a smaller trial, and then a larger trial after the fact has to be conducted to prove that it's safe and effective.

And that's what happened with the breast cancer drug, Avastin.

It made it onto the market based on a smaller trial that showed that women who had metastatic breast cancer, who received Avastin, had a six-month greater period of their cancer not worsening than women who didn't get the drug.

Not that they live longer, but that their breast cancer didn't worsen.

Unfortunately, the follow-up trials of that drug for Avastin, which are legislated by law, that have to be conducted, not only didn't show that six-month advantage, that six-month advantage dwindled to just a few weeks of women living without their breast cancer worsening.

But in one study, women actually lived less when they got Avastin than women who didn't get Avastin.

Now, just as the FDA has the ability to conduct accelerated approval to get a drug approved, they can also enact what is now referred to as accelerated withdrawal to pull the drug from the market.

So, the FDA went to the manufacturer of Avastin, Genentech, and said to them, "Your drug doesn't work, and it's probably not safe, and you need to pull it from the market."

And a company has the legal right to say, "No, we're not gonna do that."

When that happens, it leads to what's essentially a court trial in the FDA buildings between the FDA lawyers and the company lawyers with a jury convened.

And the jury in this case was the Oncologic Drugs Advisory Committee, for which I was a member.

So, the thread of the book, the thrust, the culmination was this trial about whether or not the FDA could mandate pulling a breast cancer drug from the market because it didn't work and it wasn't safe, versus a company's right to keep it on the market.

- What's the burden feel like, sitting on that panel?

And one of the powerful parts of the book are the accounts that you've shared from some of the advocates from, you know, cancer survivors, women suffering with cancer, and advocacy organizations around them, who were making the case that this drug was keeping them alive.

What's the burden like for you, sitting on that panel that's ultimately making the decision that these people, anyways, feel is life and death?

- Well, so one of the unique aspects of regulatory bodies like the FDA in the United States is that it's a completely transparent process, as opposed to some regulatory bodies in Europe where it happens behind closed doors.

So, anybody in the country can listen in real time to debates that occur at the FDA, including the Oncologic Drugs Advisory Committee as it's making decisions about cancer drugs.

And anybody in the country can actually go to the FDA and have three or four minutes to talk about a drug and why they believe that drug should be approved or not approved, or even pulled from the market.

And one of the remarkable aspects of these proceedings, this was big news at the time, were 36 women who came up to the microphone to talk about their lives with Avastin.

It was incredibly moving.

And I will tell you that, as a member of an FDA body like the Oncologic Drugs Advisory Committee, we really sit and think long and hard about the health of the public, the safety of the public, and the need for a new drug to fight cancer.

I will tell you, it's an incredible burden.

And I never served in the military, but I did look at my time at the FDA as my service to my country, to try to help make those decisions.

These women's stories were incredibly moving.

Some even brought photo albums they held up to show what their lives were like since they were diagnosed with metastatic breast cancer and treated with this drug, but also with another chemotherapy drug.

The drug was never given on its own.

So, it was always given with another chemotherapy drug, which made it very difficult to determine in an individual person, was that person benefiting from the drug Avastin, or were they benefiting from the other chemotherapy that they received?

So, incredibly moving stories.

I will add: one of the points that a member of the FDA made was that we were hearing from the women who were still alive while taking Avastin; we weren't hearing from the women who died while taking Avastin.

And she then told some of those stories about women, for example, who had bleeds in their head and died while they were on Avastin, or bleeds in their belly while they were on Avastin; both events that were attributed to the drug.

- And there there were some other people who also testified that this drug should not be on the market.

Talk about those others.

A couple were really surprising to you, that represented national groups.

- There are patient advocacy groups, which are really wonderful organizations.

And I think my disclosure is I chair the medical advisory board of one patient advocacy group, the Aplastic Anemia and MDS International Foundation.

These are really important bodies that work on behalf of patients, and they can work on behalf of patients to make sure that patients get connected to doctors who specialize, for example, in rare diseases.

They can work on behalf of patients with a legislative body and advocate for funding, for research in these rare diseases.

In this case, some of those patient advocacy groups stepped up to the microphone to say, "You know what?

We reviewed these data, and we don't think Avastin should remain on the market.

We think it's too dangerous, and we don't think it helps our patients.

So, as a patient advocacy group representing our patients, we agree with the FDA, the drug should be removed."

- You know, Mikkael, when you mentioned that, you know, this is essentially a hearing between the FDA and the company who's the maker of the drug; in this case, Genentech.

What role did Genentech's leaders play in this particular hearing?

- So, people very high up in Genentech were at the hearing itself.

And let's put a little bit of an economic spin on this story.

Avastin was a billion-dollar a-year drug for breast cancer for Genentech; billion with a B.

And this is 15 years ago.

So, you have a drug that is making a lot of money for a company.

And so, their leaders were at these hearings, and actually one wrote a letter to the editor of the New York Times, right beforehand, advocating for keeping the drug on the market because of how it was helping women, or at least how he said it was helping women.

Genentech's position was that the drug should remain on the market so they could conduct one more trial that would finally show that Avastin is really beneficial to women with breast cancer.

And they kept talking about this magical one more trial they wanted to conduct, and could the FDA leave the drug on the market just long enough so they could conduct this trial?

Well, eventually, this trial was conducted, and guess what?

It again showed absolutely no advantage for the drug Avastin.

So, part of their position was they really believed the drug worked, and frankly, there probably were individuals who benefited from Avastin.

But when you're thinking like the FDA, like a regulatory body that's thinking about the public health, and this was true during COVID also, you need to think about the safety of the population as a whole in the United States.

And whereas one person could benefit from Avastin, thousands of people not only wouldn't benefit but could be harmed by the drug.

- I think that one of the things that, at least that I was grappling with as I was reading this book, was the difference... we're not, as human beings, computers, and the same input on each of us doesn't produce the same output in each of us.

I mean, a very ham-handed, but is that an accurate description of the challenge with pharmaceutical interventions in individual patients?

- Yeah, there's a little bit of schadenfreude in how we talk about pharmaceuticals and, for example, targeted therapy.

We hear a lot about targeted therapy and personalized therapy.

And it is true that one of the greatest revolutions in cancer care that we've had in the past 15 years has been recognizing that genetic mutations are driving cancers, and we've developed drugs to target those mutations.

What people don't talk about as much is that not everybody has those mutations, and in fact, often it's a minority of patients with a given cancer diagnosis who has a mutation who will benefit from a targeted therapy.

And much of the time, those targeted therapies don't cure people.

So, eventually the cancer develops an escape mechanism where the targeted therapy doesn't work anymore.

So, we're still developing drugs that are...

I guess you would call them dumb drugs, right?

They don't target a specific abnormality, they kill cancer writ large.

But maybe we need that writ large for certain types of cancers, as opposed to targeted therapy that benefit the few.

So, it is true that we are not sophisticated enough to really understand which individual women will benefit from a drug like Avastin and which won't.

And this was one of the issues that was raised during this hearing, that there was no way that any scientist or the manufacturer itself had identified any super responder to Avastin.

- That's interesting.

You know, Mikkael, we live in a time where the government as a whole is questioned by a large segment of the population, at least a substantial segment of the population.

We also are in the aftermath of the opioid epidemic, and we know a little bit about the role of Purdue Pharma and its relationship with the FDA.

How can the public have confidence that the decisions that FDA advisory panels make are really in the best interest of the public good?

- Yeah, another great question.

I really think the FDA tries to get it right.

My experience with the FDA, and I continue to collaborate with the FDA, is that they really look long and hard at the science.

They really wanna understand the experience of an individual person with a diagnosis like cancer, and they really wanna make sure that a drug that's prescribed not just by a specialist like me; right, I spend my entire life thinking about how to treat people successfully with leukemia; but also a person who's more of a generalist.

How is that person going to prescribe the right drug and be able to manage the side effects to that drug in an individual person?

So, I really think the FDA tries to get it right.

I think where the FDA could do a better job, and especially bodies like the CDC could do a better job, is in communicating to the public where they're sure of safety and efficacy signals and where they're still not sure.

So, one of the things I've been advocating for is that when we have a drug label, which is like an instruction manual on how to give a drug and what side effects to expect, what dose to give.

On a drug label, there should be a huge fat asterisk for drugs that are approved under the accelerated approval mechanism.

And that asterisk should say, "This drug has been approved to the best of our knowledge so far and deemed to be safe and effective, but more data are coming, and we may change our recommendations."

- So, Mikkael, we only have about a minute left.

The hearing ended, the jury voted, then five months later, the FDA made a decision.

Can you give us a brief summary of that?

- We voted, and we voted unanimously that the drug should be pulled from the market.

We truly believed that it was hurting women and it wasn't benefiting women.

And then, the scene at the FDA turned into something out of a movie.

Armed guards rushed our table; women crowded around, chanting, sobbing that the drug had been removed; Others congratulating us for making a tough decision.

And we were whisked out of the FDA to a tinted window limousine and rushed off to the airport to get away from the crowds.

We were told to unlist our numbers.

We were told we would probably get death threats.

And it was actually viewed as kind of a dangerous time.

The FDA, based on that vote, did come out with a ruling that Avastin would be removed for a breast cancer indication.

But Avastin did remain on the market for other cancer indications.

So, technically it was still possible for a woman to get Avastin for breast cancer off-label, although major groups that write guidelines for how to treat breast cancer did remove their recommendations for Avastin for breast cancer.

- Mikkael Sekeres, this is a fascinating conversation and a fascinating book, "Drugs and the FDA".

Thank you so much for spending some time with us today.

- [Mikkael Sekeres] Thank you.

- That is all the time we have this week, but if you wanna know more about "Story in the Public Square", you can find us on social media or visit pellcenter.org where you can always catch up on previous episodes.

For G. Wayne Miller, I'm Jim Ludes, asking you to join us again next time for more "Story in the Public Square".

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