Drug Researchers Refuse To Follow The Law. The Government Isn’t Stopping Them.

IRA FLATOW: This is Science Friday. I’m Ira Flatow. It takes a long time before a drug can make its way into your medicine cabinet, and there’s a good reason for that. Researchers have to recruit human subjects for a clinical trial, then collect all the data and analyze the results, and all of that can take years to complete.

But the end result could be a drug candidate that treats a rare disease or improves patients’ lives with fewer side effects or it could result in a drug that doesn’t have any effect on a disease or makes patient worse or is an absolute failure. Currently, there are over 100,000 of these clinical drug trials happening in the US that can be found listed on a website, clinicaltrials.gov, a public-facing website where researchers are required by law to register all clinical trials and report the results.

This ensures that, either way, if a drug candidate fails or becomes the next big thing, the public is kept informed, except two recent investigations of clinicaltrials.gov reporting practices show that many researchers aren’t posting– they are not posting their results on the site. In fact, up to 25% of the studies never seem to have their results reported anywhere. Even worse, government agencies are not enforcing the law in ways they’ve promised, with heavy fines and threats to withhold funding from institutions that do not comply.

What does this mean for safety of our drug trials? And why has the government done nothing to crack down on researchers breaking the law? Joining me to talk about this is Charles Piller, a journalist who conducted one of the investigations of the clinicaltrials.gov for Science Magazine. He joins us by Skype. Welcome to Science Friday.

CHARLES PILLER: Thanks very much, Ira. Glad to be here.

IRA FLATOW: Nice to have you. Dr. Deborah Zarin is part of the Multi-Regional Clinical Trial Center at the Brigham and Women’s Hospital in Boston. Welcome to Science Friday.

DEBORAH ZARIN: Thank you. Happy to be here.

IRA FLATOW: Nice to have you. Charles, you’ve investigated this for Science Magazine. Give us a picture of what you uncovered.

CHARLES PILLER: Well, the picture is not very pretty. This is a law that requires the registration and reporting of drug and device trial results, and it’s critical to evidence-based medicine and for a variety of other reasons, including honoring the contributions of volunteers who, at some personal risk, agree to be the test subjects for these trials.

And what I found was that, although there has been some improvement by some organizations, particularly, as it happens, large pharma companies over the last few years, in reporting the results of their trials, there’s been a terrible deficit in that reporting by some of the leading academic organizations, some of the most eminent medical centers in the country.

And one I’ll just note, in particular, is MD Anderson Cancer Center. So this is obviously one of the most important research organizations in the country, well known for its work on immunotherapy and other kinds of cancer trials. And one of the former executives at MD Anderson, who was heading up their program is now FDA commissioner. That’s Stephen Hahn. And they had a terrible record for reporting, worse than many of the most important academic medical centers in the country.

IRA FLATOW: So I know from your reporting that about a third, 31.6%, of completed trials have not had their results posted.

CHARLES PILLER: That’s right. And I want to make it clear that this is a very conservative look we did at clinicaltrials.gov reporting. When I say conservative, what I mean is that there are hundreds of thousands of trials that are registered on the site, but because of a variety of legal and regulatory changes over the years, there’s really just a small percentage of those that are right now, according to the government– and when I said the government, I mean FDA and the National Institutes of Health– according to those two very important agencies that regulate this system, only a tiny fraction of those studies are legally reported to provide the results by about now.

And when we took a look at this data– this was back in September– it was about 4,700 clinical trials that were really needed to report their results by that time. And, as you say, of those, almost a third had not reported any data, and even worse part of the picture is that even among the ones that were reported, many of them were reported late, far at the deadline– so in essence, delaying the time when doctors, patients, and other researchers can gain access to that information.

IRA FLATOW: Dr. Zarin, can you give us a history of this law? Why did we need this law? How come it took till 2007 to get it on the books?

DEBORAH ZARIN: Sure. And let me make sure your listeners know that you mentioned my current position, but I was the director of clinicaltrials.gov from 2005 to 2018. So I was living this experience.

It used to be that investigators, whether from a drug company or in academia, would do a clinical trial, they could decide whether, when, and how to report the results of those trials. So the way to report them was in the published literature, but nobody was looking to make sure that they were published. And we now know that many weren’t published. For example, drug companies might have done nine or 10 studies of a particular drug and only published the one that came out to their liking.

Another story is that a drug company or an academic might conduct a trial and publish it but distort what the original protocol said or how they conveyed what was done in the trial. And even though it was in the peer-reviewed literature, the journal editors had no way to know that this wasn’t true because there was no other record about what the trial was or that it existed.

Academic researchers, we now know, only published about half of the trials that they conducted. For whatever reasons, they just didn’t publish the trials. And the thing is that it used to be that people like Charles Piller couldn’t have done the public audit that he’s done because there was no list of trials. So if they didn’t publish, you didn’t even know they existed.

So Congress passed the law that’s fondly known as FDAA, the Food and Drug Administration Act, to rectify this problem for drug and device studies. And I just want to say, even though I agree with Charles that compliance is nowhere near what we want it to be, it’s had a huge impact.

So trials are, in general, being registered, which is, again, why these kinds of public audits can be done, because we have a pretty good list of all the trials that are initiated. And over 40,000 sets of trial results are in clinicaltrials.gov, and about half of those are results that aren’t in the published literature. So there would be no other way of knowing those results without clinicaltrials.gov.

But that being said, it’s completely unethical to do a trial and not report the results because the only reason that society lets researchers experiment on their fellow humans is so that the results are made available for the medical community to use those results to inform either medical or scientific decisions. If those results aren’t made available, there was no justification for including people in that trial, and that’s an unethical situation.

IRA FLATOW: Well, let’s talk about the watchdog. Supposedly the government’s supposed to be a watchdog on publishing these things and is supposed to have fines and things for the people who don’t publish them, Dr. Zarin. Why have we not seen a rash of justice come down on this?

DEBORAH ZARIN: That’s a really tough question. And again, I’m not the one in charge of enforcement. I suppose if I was, the picture would look quite different. So first, there was a long wait until the final rule, or the regulations, were enacted, and those took effect in 2017 because the regulations clarified all sorts of details about this very complicated law.

And at that time, as Charles mentioned in the article that he published, the leaders of those organizations– it was Dr. Califf at the FDA and Dr. Collins at NIH. Dr. Collins is still the head of NIH– made very strong statements that they were going to enforce. And it’s very disappointing to me that they haven’t done any enforcement. I think there are probably many reasons for that, but I find it unacceptable.

IRA FLATOW: Let me ask Dr. Piller. What reasons do you think there are for that, Charles?

CHARLES PILLER: Thank you for that, elevating my status–

IRA FLATOW: I’m sorry.

CHARLES PILLER: –to being a doctor.

IRA FLATOW: Well, I’m not sorry.

CHARLES PILLER: But, yes, there are many reasons for it. According to both NIH and FDA, they believe in, quote, unquote, “voluntary compliance.” They want to use moral suasion. They want to urge trial investigators to do the right thing. Unfortunately, what we’ve seen is that, over the last five years, that method, while it has some limited effectiveness, is really not what moves the needle in getting people to do the right thing and report their results.

And I say this advisedly in part because I’ve been writing investigations about this topic since 2015, and the first one I did was with STAT, the medical and biomedical research news website. And what we found was that the situation was even worse back then, back in 2015, that there was a horrific record of trial reporting by all kinds of sponsors, both corporate and academic.

And what we did for the first time is name names to talk about the institutions that were the worst lawbreakers, the ones who seemed to show the least care about presenting the data associated with these important trials. And what we found was that that did, indeed, have an impact. There was an improvement in trial reporting.

Now, it wasn’t, obviously, not exclusively due to that sort of reporting. NIH’s efforts have been heroic in trying to educate researchers on how to do this better, and I credit them as well. But I think what we know from experience is that naming and shaming the scofflaws often has the most serious impact on this in the absence of enforcement.

So why isn’t there enforcement? And it’s really a perplexing question because the comments coming, as Deborah mentioned, the comments coming from the heads of FDA and NIH in 2016 when they announced this so-called final rule associated with this law was meant to just put people on notice. You’ve got years to prepare for this, years to ensure that your studies are now being reported effectively. And so now, years later, we take a look, and they’re not being reported, and NIH and FDA are essentially doing nothing to enforce the law.

IRA FLATOW: But some academic medical centers have stepped up to be in line with the law.

CHARLES PILLER: Indeed, indeed, and that’s very encouraging. Now, I don’t want to paint too bleak a picture. Let’s talk on the positive side for a moment. Institutions, like some of the major pharma companies, are following the letter of the law. In other words, for the most part, they’re reporting all their results within the legal deadlines.

Some leading academic medical centers, such as Memorial Sloan Kettering, Duke University, Johns Hopkins, who were poor performers when I last took a look at this issue a couple years ago, they are now doing much better and, for the most part, are complying with the requirements of the law and the ethical requirements of reporting their results.

But I think it– just to caution listeners for one moment about what it means in particular for the drug companies that seem to have a kind of perfect record in following the law. There are many loopholes in the law that allow entities that are working towards approval, FDA approval to put a drug on the market, to withhold trial information from the public, and those are meant generally to protect proprietary information, trade secrecy, to prevent competitors from getting a leg up on them.

And it’s understandable that that would be protected for some time, but it’s been found in other studies that a lot of times the drug companies never report the results of those trials to clinicaltrials.gov. So the only way to even learn what happened is to dig deep into the FDA drug approval packages, which are really well beyond the capacity or the ability of 99.9% of doctors, let alone patients and general public.

IRA FLATOW: Let me just break in and say I’m Ira Flatow. This is Science Friday from WNYC Studios. So even while they’re reporting, you have to really dig in there to find them. You mentioned these drugs, and you singled doubt MD Anderson, very well-known cancer center in Houston. Are you naming and shaming them today?

CHARLES PILLER: Well, indeed. And in the article, some of the institutions that we think of as being the most eminent in the country, the most important progenitors of clinical research in the country, including MD Anderson, Mass General, Mayo Clinic, and others, have had really next to terrible records in reporting their results.

And one of the reasons I single some of those out– we’ll just take MD Anderson as an example. They have the highest number of clinical trials due for reporting under the new so-called final rule that we looked at for this story more than any other institution.

And I looked at their performance years ago, and I found that they actually did worse now than they did years ago in reporting the results of their trials. So that’s a pretty troubling piece of data.

IRA FLATOW: Let me break in and ask Dr. Zarin how she would think how you would incentivize academic medical centers to be more compliant.

DEBORAH ZARIN: Well, that’s a really good question, and, of course, I’ve thought a lot about it. What you’d like is leadership to understand that reporting your results of your trials is both a scientific and an ethical imperative. And we don’t see much of that.

Sometimes at academic medical centers, at least from their public statements, what you see is not wanting to be on the wall of shame. So you see them saying, it’s a law, you have to do it, which works, but isn’t as good as saying, not only do you have to do it, but there’s a really important reason that you have to do it.

I like to compare it to the regulations that require that we get informed consent from every trial participant. Imagine if there was an academic medical center that had 80% compliance with that particular requirement. Would they be proud of that? Would society stand for the fact that 20% of their trial participants didn’t even give informed consent? And yet, being in a trial that has no chance of advancing medical science is, to me, equally as unethical as not giving informed consent to be in a trial. So it’s important to think about that.

So without the leadership of your academic medical center caring about whether you do this, other than whether you’re going to get caught and shamed or, worse yet, actually enforced, I think there needs to be both enforcement by our government agencies, FDA and NIH, and we need people like Charles Piller to keep holding people accountable.

I think public accountability, which, again, is possible because, in general, people are registering their trials, so you can get that list of trials from clinicaltrials.gov– public accountability is probably where we have to go and really make it very uncomfortable for institutions to be out of compliance.

IRA FLATOW: Well, we’ve given you a little platform to allow the public to know what’s going on. I don’t think this is something they were very much aware of and how much it impacts research. Thank you, Dr. Zarin, Deborah Zarin, part of the Multi-Regional Clinical Center at Brigham and Women’s Hospital in Boston and who was also a part of the clinicaltrials.gov organization, Charles Piller, investigative journalist for Science Magazine. Thank you both for taking time to be with us today.

DEBORAH ZARIN: Thank you so much.

CHARLES PILLER: Thanks, Ira.

IRA FLATOW: You’re welcome.

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